bims-medica 2023-10-29 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2023–10–29
38 papers selected by
Brett Chrest, East Carolina University

Lactate activates the mitochondrial electron transport chain independently of its metabolism.
Role of Oxidative Stress in Metabolic Reprogramming of Brain Cancer.
Dissecting the Role of Autophagy-Related Proteins in Cancer Metabolism and Plasticity.
Mitochondrial complex I ROS production and redox signaling in hypoxia.
Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells.
Innate lymphoid cells and tumor-derived lactic acid: novel contenders in an enduring game.
The connection between tricarboxylic acid cycle enzyme mutations and pseudohypoxic signaling in pheochromocytoma and paraganglioma.
Ketone Bodies in Diabetes Mellitus: Friend or Foe?
G6PD Maintains Redox Homeostasis and Biosynthesis in LKB1-Deficient KRAS-Driven Lung Cancer.
How protons pave the way to aggressive cancers.
Ketogenic Diet and Breast Cancer: Recent Findings and Therapeutic Approaches.
Proline metabolism shapes the tumor microenvironment: from collagen deposition to immune evasion.
The Significance of Microenvironmental and Circulating Lactate in Breast Cancer.
Novel Therapeutic Strategies Exploiting the Unique Properties of Neuroendocrine Neoplasms.
The ketone body β-hydroxybutyrate shifts microglial metabolism and suppresses amyloid-β oligomer-induced inflammation in human microglia.
Acetyl-CoA metabolism as a therapeutic target for cancer.
LDHA-regulated tumor-macrophage symbiosis promotes glioblastoma progression.
Monocarboxylate Transporter-1 (MCT1)-Mediated Lactate Uptake Protects Pancreatic Adenocarcinoma Cells from Oxidative Stress during Glutamine Scarcity Thereby Promoting Resistance against Inhibitors of Glutamine Metabolism.
Proteomic profiling and network biology of colorectal cancer liver metastasis.
Copper-mediated novel cell death pathway in tumor cells and implications for innovative cancer therapies.
Integration with Transcriptomic and Metabolomic Analyses Reveals the In Vitro Cytotoxic Mechanisms of Chinese Poplar Propolis by Triggering the Glucose Metabolism in Human Hepatocellular Carcinoma Cells.
A Simple and Fast Method for the Formation and Downstream Processing of Cancer-Cell-Derived 3D Spheroids: An Example Using Nicotine-Treated A549 Lung Cancer 3D Spheres.
Controlling pericellular oxygen tension in cell culture reveals distinct breast cancer responses to low oxygen tensions.
A genetically encoded tool to increase cellular NADH/NAD+ ratio in living cells.
Adaptation to volumetric compression drives hepatoblastoma cells to an apoptosis-resistant and invasive phenotype.
Exploring cell cycle-mediated regulations of glycolysis in budding yeast.
ASCT2 is the primary serine transporter in cancer cells.
Diet-induced diabetes is associated with lower hippocampal glycogen and reduced glycogenolysis following local exogenous insulin.
Current knowledge and potential intervention of hexosamine biosynthesis pathway in lung cancer.
A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer.
Integration of metabolomics and transcriptomics reveals metformin suppresses thyroid cancer progression via inhibiting glycolysis and restraining DNA replication.
Comparative analysis between 2D and 3D colorectal cancer culture models for insights into cellular morphological and transcriptomic variations.
Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium.
Beyond energy and growth: the role of metabolism in developmental signaling, cell behavior and diapause.
Ketogenic Diet Exacerbates L-Arginine-Induced Acute Pancreatitis and Reveals the Therapeutic Potential of Butyrate.
Ketogenic diet influence on the elemental homeostasis of internal organs is gender dependent.
Phospholipid metabolic adaptation promotes survival of IDH2 mutant acute myeloid leukemia cells.

Mol Cell. 2023 Oct 20. pii: S1097-2765(23)00800-6. [Epub ahead of print]

Lactate activates the mitochondrial electron transport chain independently of its metabolism.

Xin Cai, Charles P Ng, Olivia Jones, Tak Shun Fung, Keun Woo Ryu, Dayi Li, Craig B Thompson.

  Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.

Keywords:  TCA cycle; electron transport chain; glycolysis; lactate; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.molcel.2023.09.034
Cancers (Basel). 2023 Oct 10. pii: 4920. [Epub ahead of print]15(20):

Role of Oxidative Stress in Metabolic Reprogramming of Brain Cancer.

Kirti Agrawal, Shailendra Asthana, Dhruv Kumar.

  Brain cancer is known as one of the deadliest cancers globally. One of the causative factors is the imbalance between oxidative and antioxidant activities in the body, which is referred to as oxidative stress (OS). As part of regular metabolism, oxygen is reduced by electrons, resulting in the creation of numerous reactive oxygen species (ROS). Inflammation is intricately associated with the generation of OS, leading to the increased production and accumulation of reactive oxygen and nitrogen species (RONS). Glioma stands out as one of the most common malignant tumors affecting the central nervous system (CNS), characterized by changes in the redox balance. Brain cancer cells exhibit inherent resistance to most conventional treatments, primarily due to the distinctive tumor microenvironment. Oxidative stress (OS) plays a crucial role in the development of various brain-related malignancies, such as glioblastoma multiforme (GBM) and medulloblastoma, where OS significantly disrupts the normal homeostasis of the brain. In this review, we provide in-depth descriptions of prospective targets and therapeutics, along with an assessment of OS and its impact on brain cancer metabolism. We also discuss targeted therapies.

Keywords:  RNS; RONS; ROS; brain cancer; oxidative stress; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers15204920
Cells. 2023 Oct 19. pii: 2486. [Epub ahead of print]12(20):

Dissecting the Role of Autophagy-Related Proteins in Cancer Metabolism and Plasticity.

Liliana Torres-López, Oxana Dobrovinskaya.

  Modulation of autophagy as an anticancer strategy has been widely studied and evaluated in several cell models. However, little attention has been paid to the metabolic changes that occur in a cancer cell when autophagy is inhibited or induced. In this review, we describe how the expression and regulation of various autophagy-related (ATGs) genes and proteins are associated with cancer progression and cancer plasticity. We present a comprehensive review of how deregulation of ATGs affects cancer cell metabolism, where inhibition of autophagy is mainly reflected in the enhancement of the Warburg effect. The importance of metabolic changes, which largely depend on the cancer type and form part of a cancer cell's escape strategy after autophagy modulation, is emphasized. Consequently, pharmacological strategies based on a dual inhibition of metabolic and autophagy pathways emerged and are reviewed critically here.

Keywords:  Warburg effect; aerobic glycolysis; autophagy; autophagy-related (ATGs) genes/proteins; cancer cell metabolism; cancer plasticity; fatty acid oxidation (FAO); tumor microenvironment

DOI:  https://doi.org/10.3390/cells12202486
Redox Biol. 2023 Oct 16. pii: S2213-2317(23)00327-0. [Epub ahead of print]67 102926

Mitochondrial complex I ROS production and redox signaling in hypoxia.

Chidozie N Okoye, Shon A Koren, Andrew P Wojtovich.

  Mitochondria are a main source of cellular energy. Oxidative phosphorylation (OXPHOS) is the major process of aerobic respiration. Enzyme complexes of the electron transport chain (ETC) pump protons to generate a protonmotive force (Δp) that drives OXPHOS. Complex I is an electron entry point into the ETC. Complex I oxidizes nicotinamide adenine dinucleotide (NADH) and transfers electrons to ubiquinone in a reaction coupled with proton pumping. Complex I also produces reactive oxygen species (ROS) under various conditions. The enzymatic activities of complex I can be regulated by metabolic conditions and serves as a regulatory node of the ETC. Complex I ROS plays diverse roles in cell metabolism ranging from physiologic to pathologic conditions. Progress in our understanding indicates that ROS release from complex I serves important signaling functions. Increasing evidence suggests that complex I ROS is important in signaling a mismatch in energy production and demand. In this article, we review the role of ROS from complex I in sensing acute hypoxia.

Keywords:  Acute hypoxia; Mitochondrial complex I; Oxygen sensing; ROS signaling

DOI:  https://doi.org/10.1016/j.redox.2023.102926
Biomedicines. 2023 Oct 19. pii: 2842. [Epub ahead of print]11(10):

Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells.

Jie Zhang, Mark A Keibler, Wentao Dong, Jenny Ghelfi, Thekla Cordes, Tamara Kanashova, Arnaud Pailot, Carole L Linster, Gunnar Dittmar, Christian M Metallo, Tim Lautenschlaeger, Karsten Hiller, Gregory Stephanopoulos.

  Using an untargeted stable isotope-assisted metabolomics approach, we identify erythronate as a metabolite that accumulates in several human cancer cell lines. Erythronate has been reported to be a detoxification product derived from off-target glycolytic metabolism. We use chemical inhibitors and genetic silencing to define the pentose phosphate pathway intermediate erythrose 4-phosphate (E4P) as the starting substrate for erythronate production. However, following enzyme assay-coupled protein fractionation and subsequent proteomics analysis, we identify aldehyde dehydrogenase 1A1 (ALDH1A1) as the predominant contributor to erythrose oxidation to erythronate in cell extracts. Through modulating ALDH1A1 expression in cancer cell lines, we provide additional support. We hence describe a possible alternative route to erythronate production involving the dephosphorylation of E4P to form erythrose, followed by its oxidation by ALDH1A1. Finally, we measure increased erythronate concentrations in tumors relative to adjacent normal tissues from lung cancer patients. These findings suggest the accumulation of erythronate to be an example of metabolic reprogramming in cancer cells, raising the possibility that elevated levels of erythronate may serve as a biomarker of certain types of cancer.

Keywords:  aldehyde dehydrogenase 1A1 (ALDH1A1); cancer metabolism; erythronate; pentose phosphate pathway; untargeted metabolomics

DOI:  https://doi.org/10.3390/biomedicines11102842
Front Immunol. 2023 ;14 1236301

Innate lymphoid cells and tumor-derived lactic acid: novel contenders in an enduring game.

Mateusz Marciniak, Marek Wagner.

  Aerobic glycolysis, also known as the Warburg effect, has for a prolonged period of time been perceived as a defining feature of tumor metabolism. The redirection of glucose utilization towards increased production of lactate by cancer cells enables their rapid proliferation, unceasing growth, and longevity. At the same time, it serves as a significant contributor to acidification of the tumor microenvironment, which, in turn, imposes substantial constraints on infiltrating immune cells. Here, we delve into the influence of tumor-derived lactic acid on innate lymphoid cells (ILCs) and discuss potential therapeutic approaches. Given the abundance of ILCs in barrier tissues such as the skin, we provide insights aimed at translating this knowledge into therapies that may specifically target skin cancer.

Keywords:  innate lymphoid cells; lactate; lactic acid; melanoma; metabolism; skin; skin cancer

DOI:  https://doi.org/10.3389/fimmu.2023.1236301
Front Endocrinol (Lausanne). 2023 ;14 1274239

The connection between tricarboxylic acid cycle enzyme mutations and pseudohypoxic signaling in pheochromocytoma and paraganglioma.

Yuxiong Wang, Bin Liu, Faping Li, Yanghe Zhang, Xin Gao, Yishu Wang, Honglan Zhou.

  Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their capacity for excessive catecholamine secretion and associated cardiovascular complications. Roughly 80% of cases are associated with genetic mutations. Based on the functionality of these mutated genes, PPGLs can be categorized into distinct molecular clusters: the pseudohypoxia signaling cluster (Cluster-1), the kinase signaling cluster (Cluster-2), and the WNT signaling cluster (Cluster-3). A pivotal factor in the pathogenesis of PPGLs is hypoxia-inducible factor-2α (HIF2α), which becomes upregulated even under normoxic conditions, activating downstream transcriptional processes associated with pseudohypoxia. This adaptation provides tumor cells with a growth advantage and enhances their ability to thrive in adverse microenvironments. Moreover, pseudohypoxia disrupts immune cell communication, leading to the development of an immunosuppressive tumor microenvironment. Within Cluster-1a, metabolic perturbations are particularly pronounced. Mutations in enzymes associated with the tricarboxylic acid (TCA) cycle, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH), isocitrate dehydrogenase (IDH), and malate dehydrogenase type 2 (MDH2), result in the accumulation of critical oncogenic metabolic intermediates. Notable among these intermediates are succinate, fumarate, and 2-hydroxyglutarate (2-HG), which promote activation of the HIFs signaling pathway through various mechanisms, thus inducing pseudohypoxia and facilitating tumorigenesis. SDHx mutations are prevalent in PPGLs, disrupting mitochondrial function and causing succinate accumulation, which competitively inhibits α-ketoglutarate-dependent dioxygenases. Consequently, this leads to global hypermethylation, epigenetic changes, and activation of HIFs. In FH-deficient cells, fumarate accumulation leads to protein succination, impacting cell function. FH mutations also trigger metabolic reprogramming towards glycolysis and lactate synthesis. IDH1/2 mutations generate D-2HG, inhibiting α-ketoglutarate-dependent dioxygenases and stabilizing HIFs. Similarly, MDH2 mutations are associated with HIF stability and pseudohypoxic response. Understanding the intricate relationship between metabolic enzyme mutations in the TCA cycle and pseudohypoxic signaling is crucial for unraveling the pathogenesis of PPGLs and developing targeted therapies. This knowledge enhances our comprehension of the pivotal role of cellular metabolism in PPGLs and holds implications for potential therapeutic advancements.

Keywords:  VHL/HIF axis; genetic mutations; metabolic reprogramming; paraganglioma; pheochromocytoma; pseudohypoxia; tricarboxylic acid cycle

DOI:  https://doi.org/10.3389/fendo.2023.1274239
Nutrients. 2023 Oct 16. pii: 4383. [Epub ahead of print]15(20):

Ketone Bodies in Diabetes Mellitus: Friend or Foe?

Stavroula Veneti, Maria G Grammatikopoulou, Evangelia Kintiraki, Gesthimani Mintziori, Dimitrios G Goulis.

  In glucose-deprived conditions, ketone bodies are produced by the liver mitochondria, through the catabolism of fatty acids, and are used peripherally, as an alternative energy source. Ketones are produced in the body under normal conditions, including during pregnancy and the neonatal period, when following a ketogenic diet (KD), fasting, or exercising. Additionally, ketone synthesis is also augmented under pathological conditions, including cases of diabetic ketoacidosis (DKA), alcoholism, and several metabolic disorders. Nonetheless, diet is the main regulator of total body ketone concentrations. The KDs are mimicking the fasting state, altering the default metabolism towards the use of ketones as the primary fuel source. Recently, KD has gained recognition as a medical nutrition therapy for a plethora of metabolic conditions, including obesity and diabetes mellitus (DM). The present review aims to discuss the role of ketones, KDs, ketonemia, and ketonuria in DM, presenting all the available new evidence in a comprehensive manner.

Keywords:  acetoacetate; carbohydrate restriction; low glycemic index; low-carbohydrate diet; middle-chain triglycerides; obesity; prediabetes; weight loss; β-hydroxybutyrate

DOI:  https://doi.org/10.3390/nu15204383
bioRxiv. 2023 Oct 09. pii: 2023.10.06.561131. [Epub ahead of print]

G6PD Maintains Redox Homeostasis and Biosynthesis in LKB1-Deficient KRAS-Driven Lung Cancer.

Taijin Lan, Sara Arastu, Samuel Wang, Jarrick Lam, Wenping Wang, Vrushank Bhatt, Eduardo Cararo Lopes, Zhixian Hu, Michael Sun, Xuefei Luo, Jonathan M Ghergurovich, Changlong Li, Xiaoyang Su, Joshua D Rabinowitz, Eileen White, Jessie Yanxiang Guo.

Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NAPDH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer model, we show that ablation of G6PD significantly suppresses Kras G12D/+ ;Lkb1 -/- (KL) but not Kras G12D/+ ;p53 -/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics revealed that G6PD ablation significantly impaired NADPH generation, redox balance and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation caused p53 activation that suppressed tumor growth. As tumor progressed, G6PD-deficient KL tumors increased an alternative NADPH source, serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.

DOI: https://doi.org/10.1101/2023.10.06.561131
Nat Rev Cancer. 2023 Oct 26.

How protons pave the way to aggressive cancers.

Pawel Swietach, Ebbe Boedtkjer, Stine Falsig Pedersen.

Cancers undergo sequential changes to proton (H+) concentration and sensing that are consequences of the disease and facilitate its further progression. The impact of protonation state on protein activity can arise from alterations to amino acids or their titration. Indeed, many cancer-initiating mutations influence pH balance, regulation or sensing in a manner that enables growth and invasion outside normal constraints as part of oncogenic transformation. These cancer-supporting effects become more prominent when tumours develop an acidic microenvironment owing to metabolic reprogramming and disordered perfusion. The ensuing intracellular and extracellular pH disturbances affect multiple aspects of tumour biology, ranging from proliferation to immune surveillance, and can even facilitate further mutagenesis. As a selection pressure, extracellular acidosis accelerates disease progression by favouring acid-resistant cancer cells, which are typically associated with aggressive phenotypes. Although acid-base disturbances in tumours often occur alongside hypoxia and lactate accumulation, there is now ample evidence for a distinct role of H+-operated responses in key events underpinning cancer. The breadth of these actions presents therapeutic opportunities to change the trajectory of disease.

DOI: https://doi.org/10.1038/s41568-023-00628-9
Nutrients. 2023 Oct 13. pii: 4357. [Epub ahead of print]15(20):

Ketogenic Diet and Breast Cancer: Recent Findings and Therapeutic Approaches.

Alfio Giuseppe Urzì, Emanuela Tropea, Giuseppe Gattuso, Graziana Spoto, Gabriella Marsala, Daniela Calina, Massimo Libra, Luca Falzone.

  Breast cancer (BC), a complex disease with several influencing factors, is significantly impacted by dietary habits. The ketogenic diet (KD), characterized by high fat and low carbohydrate intake, has gained attention as a potential therapeutic approach, but its effects on BC remain unclear. This review seeks to summarize the current knowledge on the principles of the KD, its metabolic influence on BC cells, and the findings of recent clinical trials, in order to elucidate the potential therapeutic role of the KD in BC management. For these purposes, a comprehensive literature review was conducted selecting preclinical and clinical studies that investigate the relationship between the KD and BC. The selection criteria prioritized studies exploring the KD's metabolic effects on BC cells and current clinical trials involving the KD in BC management. The reviewed studies provide a diverse range of findings, with some suggesting potential benefits of the KD in inhibiting tumor growth and improving treatment response. However, robust clinical trials providing clear evidence of the KD's efficacy as a standalone therapeutic approach in BC are still lacking. There are also significant concerns regarding the safety and long-term effects of sustained ketosis in cancer patients. The therapeutic potential of the KD in BC remains an area of active research and debate. While preliminary findings are promising, definitive conclusions are hindered by inconsistent results and limited human trial data. Future research, specifically well-structured, large-scale clinical trials, is necessary to provide a comprehensive understanding of the role of the KD in BC treatment. Until then, caution should be exercised in its application, and patients should continue prioritizing evidence-based, standard-of-care treatments.

Keywords:  breast cancer; glycemic load; integrated treatments; ketogenesis; ketogenic diet; proteins

DOI:  https://doi.org/10.3390/nu15204357
Curr Opin Biotechnol. 2023 Oct 19. pii: S0958-1669(23)00121-0. [Epub ahead of print]84 103011

Proline metabolism shapes the tumor microenvironment: from collagen deposition to immune evasion.

Emily J Kay, Sara Zanivan, Alessandro Rufini.

Proline is a nonessential amino acid, and its metabolism has been implicated in numerous malignancies. Together with a direct role in regulating cancer cells' proliferation and survival, proline metabolism plays active roles in shaping the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) display high rates of proline biosynthesis to support the production of collagen for the extracellular matrix (ECM). Indeed, impaired proline metabolism in CAFs results in reduced collagen deposition and compromises the growth and metastatic spread of cancer. Moreover, the rate of proline metabolism regulates intracellular reactive oxygen species (ROS) levels, which influence the production and release of cytokines from cancer cells, contributing toward an immune-permissive TME. Hence, targeting proline metabolism is a promising anticancer strategy that could improve patients' outcome and response to immunotherapy.

DOI: https://doi.org/10.1016/j.copbio.2023.103011
Int J Mol Sci. 2023 Oct 19. pii: 15369. [Epub ahead of print]24(20):

The Significance of Microenvironmental and Circulating Lactate in Breast Cancer.

Vincenza Frisardi, Simone Canovi, Salvatore Vaccaro, Raffaele Frazzi.

  Lactate represents the main product of pyruvate reduction catalyzed by the lactic dehydrogenase family of enzymes. Cancer cells utilize great quantities of glucose, shifting toward a glycolytic metabolism. With the contribution of tumor stromal cells and under hypoxic conditions, this leads toward the acidification of the extracellular matrix. The ability to shift between different metabolic pathways is a characteristic of breast cancer cells and is associated with an aggressive phenotype. Furthermore, the preliminary scientific evidence concerning the levels of circulating lactate in breast cancer points toward a correlation between hyperlactacidemia and poor prognosis, even though no clear linkage has been demonstrated. Overall, lactate may represent a promising metabolic target that needs to be investigated in breast cancer.

Keywords:  acidosis; aerobic glycolysis; breast cancer; lactate

DOI:  https://doi.org/10.3390/ijms242015369
Cancers (Basel). 2023 Oct 12. pii: 4960. [Epub ahead of print]15(20):

Novel Therapeutic Strategies Exploiting the Unique Properties of Neuroendocrine Neoplasms.

Maryam Safari, Luigi Scotto, Thomas Litman, Lubov A Petrukhin, Hu Zhu, Min Shen, Robert W Robey, Matthew D Hall, Tito Fojo, Susan E Bates.

   BACKGROUND: Over the last few decades of treatment, the outcomes for at least some subsets of neuroendocrine neoplasms (NENs) have improved. However, the identification of new vulnerabilities for this heterogeneous group of cancers remains a priority.
METHODS: Using two libraries of compounds selected for potential repurposing, we identified the inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylases (HDAC) as the agents with the highest activity. We validated the hits in an expanded set of neuroendocrine cell lines and examined the mechanisms of action.
RESULTS: In Kelly, NH-6, and NCI-H82, which are two neuroblastoma and one small cell lung cancer cell lines, respectively, metabolic studies suggested that cell death following NAMPT inhibition is the result of a reduction in basal oxidative phosphorylation and energy production. NAMPT is the rate-limiting enzyme in the production of NAD+, and in the three cell lines, NAMPT inhibition led to a marked reduction in the ATP and NAD+ levels and the catalytic activity of the citric acid cycle. Moreover, comparative analysis of the mRNA expression in drug-sensitive and -insensitive cell lines found less dependency of the latter on oxidative phosphorylation for their energy requirement. Further, the analysis of HDAC and NAMPT inhibitors administered in combination found marked activity using low sub-lethal concentrations of both agents, suggesting a synergistic effect.
CONCLUSION: These data suggest NAMPT inhibitors alone or in combination with HDAC inhibitors could be particularly effective in the treatment of neuroendocrine neoplasms.

Keywords:  HDAC inhibitors; NAMPT inhibitors; YAP1; metabolism; neuroendocrine; neuroendocrine neoplasms

DOI:  https://doi.org/10.3390/cancers15204960
FASEB J. 2023 11;37(11): e23261

The ketone body β-hydroxybutyrate shifts microglial metabolism and suppresses amyloid-β oligomer-induced inflammation in human microglia.

Lee-Way Jin, Jacopo Di Lucente, Ulises Ruiz Mendiola, Nopparat Suthprasertporn, Alexey Tomilov, Gino Cortopassi, Kyoungmi Kim, Jon J Ramsey, Izumi Maezawa.

  Fatty acids are metabolized by β-oxidation within the "mitochondrial ketogenic pathway" (MKP) to generate β-hydroxybutyrate (BHB), a ketone body. BHB can be generated by most cells but largely by hepatocytes following exercise, fasting, or ketogenic diet consumption. BHB has been shown to modulate systemic and brain inflammation; however, its direct effects on microglia have been little studied. We investigated the impact of BHB on Aβ oligomer (AβO)-stimulated human iPS-derived microglia (hiMG), a model relevant to the pathogenesis of Alzheimer's disease (AD). HiMG responded to AβO with proinflammatory activation, which was mitigated by BHB at physiological concentrations of 0.1-2 mM. AβO stimulated glycolytic transcripts, suppressed genes in the β-oxidation pathway, and induced over-expression of AD-relevant p46Shc, an endogenous inhibitor of thiolase, actions that are expected to suppress MKP. AβO also triggered mitochondrial Ca2+ increase, mitochondrial reactive oxygen species production, and activation of the mitochondrial permeability transition pore. BHB potently ameliorated all the above mitochondrial changes and rectified the MKP, resulting in reduced inflammasome activation and recovery of the phagocytotic function impaired by AβO. These results indicate that microglia MKP can be induced to modulate microglia immunometabolism, and that BHB can remedy "keto-deficiency" resulting from MKP suppression and shift microglia away from proinflammatory mitochondrial metabolism. These effects of BHB may contribute to the beneficial effects of ketogenic diet intervention in aged mice and in human subjects with mild AD.

Keywords:  Alzheimer's; amyloid; inflammation; ketone; microglia; mitochondria; phagocytosis

DOI:  https://doi.org/10.1096/fj.202301254R
Biomed Pharmacother. 2023 Oct 19. pii: S0753-3322(23)01539-1. [Epub ahead of print]168 115741

Acetyl-CoA metabolism as a therapeutic target for cancer.

Guo Chen, Banghe Bao, Yang Cheng, Minxiu Tian, Jiyu Song, Liduan Zheng, Qiangsong Tong.

  Acetyl-coenzyme A (acetyl-CoA), an essential metabolite, not only takes part in numerous intracellular metabolic processes, powers the tricarboxylic acid cycle, serves as a key hub for the biosynthesis of fatty acids and isoprenoids, but also serves as a signaling substrate for acetylation reactions in post-translational modification of proteins, which is crucial for the epigenetic inheritance of cells. Acetyl-CoA links lipid metabolism with histone acetylation to create a more intricate regulatory system that affects the growth, aggressiveness, and drug resistance of malignancies such as glioblastoma, breast cancer, and hepatocellular carcinoma. These fascinating advances in the knowledge of acetyl-CoA metabolism during carcinogenesis and normal physiology have raised interest regarding its modulation in malignancies. In this review, we provide an overview of the regulation and cancer relevance of main metabolic pathways in which acetyl-CoA participates. We also summarize the role of acetyl-CoA in the metabolic reprogramming and stress regulation of cancer cells, as well as medical application of inhibitors targeting its dysregulation in therapeutic intervention of cancers.

Keywords:  Acetyl-coenzyme A metabolism; Cancer progression; Cancer therapy; Metabolic reprogramming; Protein acetylation

DOI:  https://doi.org/10.1016/j.biopha.2023.115741
Res Sq. 2023 Oct 05. pii: rs.3.rs-3401154. [Epub ahead of print]

LDHA-regulated tumor-macrophage symbiosis promotes glioblastoma progression.

Peiwen Chen, Fatima Khan, Yiyu Lin, Heba Ali, Lizhi Pang, Madeline Dunterman, Wen-Hao Hsu, Katie Frenis, R Grant Rowe, Derek Wainwright, Kathleen McCortney, Leah Billingham, Jason Miska, Craig Horbinski, Maciej Lesniak.

Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase (LDH) inhibitor stiripentol (an FDA-approved anti-seizure drug for Dravet Syndrome) emerges as the top hit. Combined profiling and functional studies demonstrate that LDHA-directed ERK pathway activates YAP1/STAT3 transcriptional co-activators in glioblastoma cells to upregulate CCL2 and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.

DOI: https://doi.org/10.21203/rs.3.rs-3401154/v1
Antioxidants (Basel). 2023 Sep 30. pii: 1818. [Epub ahead of print]12(10):

Monocarboxylate Transporter-1 (MCT1)-Mediated Lactate Uptake Protects Pancreatic Adenocarcinoma Cells from Oxidative Stress during Glutamine Scarcity Thereby Promoting Resistance against Inhibitors of Glutamine Metabolism.

Nourhane Ammar, Maya Hildebrandt, Claudia Geismann, Christian Röder, Timo Gemoll, Susanne Sebens, Ania Trauzold, Heiner Schäfer.

  Metabolic compartmentalization of stroma-rich tumors, like pancreatic ductal adenocarcinoma (PDAC), greatly contributes to malignancy. This involves cancer cells importing lactate from the microenvironment (reverse Warburg cells) through monocarboxylate transporter-1 (MCT1) along with substantial phenotype alterations. Here, we report that the reverse Warburg phenotype of PDAC cells compensated for the shortage of glutamine as an essential metabolite for redox homeostasis. Thus, oxidative stress caused by glutamine depletion led to an Nrf2-dependent induction of MCT1 expression in pancreatic T3M4 and A818-6 cells. Moreover, greater MCT1 expression was detected in glutamine-scarce regions within tumor tissues from PDAC patients. MCT1-driven lactate uptake supported the neutralization of reactive oxygen species excessively produced under glutamine shortage and the resulting drop in glutathione levels that were restored by the imported lactate. Consequently, PDAC cells showed greater survival and growth under glutamine depletion when utilizing lactate through MCT1. Likewise, the glutamine uptake inhibitor V9302 and glutaminase-1 inhibitor CB839 induced oxidative stress in PDAC cells, along with cell death and cell cycle arrest that were again compensated by MCT1 upregulation and forced lactate uptake. Our findings show a novel mechanism by which PDAC cells adapt their metabolism to glutamine scarcity and by which they develop resistance against anticancer treatments based on glutamine uptake/metabolism inhibition.

Keywords:  anaplerosis; drug resistance; pancreas; tumor metabolism

DOI:  https://doi.org/10.3390/antiox12101818
Expert Rev Proteomics. 2023 Oct 24. 1-14

Proteomic profiling and network biology of colorectal cancer liver metastasis.

Rubén A Bartolomé, J Ignacio Casal.

   INTRODUCTION: Tissue-based proteomic studies of colorectal cancer (CRC) metastasis have delivered fragmented results, with very few therapeutic targets and prognostic biomarkers moving beyond the discovery phase. This situation is likely due to the difficulties in obtaining and analyzing large numbers of patient-derived metastatic samples, the own heterogeneity of CRC, and technical limitations in proteomics discovery. As an alternative, metastatic CRC cell lines provide a flexible framework to investigate the underlying mechanisms and network biology of metastasis for target discovery.
AREAS COVERED: In this perspective, we comment on different in-depth proteomic studies of metastatic versus non-metastatic CRC cell lines. Identified metastasis-related proteins are introduced and discussed according to the spatial location in different cellular fractions, with special emphasis on membrane/adhesion proteins, secreted proteins, and nuclear factors, including miRNAs associated with liver metastasis. Moreover, we analyze the biological significance and potential therapeutic applications of the identified liver metastasis-related proteins.
EXPERT OPINION: The combination of protein discovery and functional analysis is the only way to accelerate the progress to clinical translation of the proteomic-derived findings in a relatively fast pace. Patient-derived organoids represent a promising alternative to patient tissues and cell lines, but further optimizations are still required for achieving solid and reproducible results.

Keywords:  Colorectal cancer; Interactomics; metastasis; quantitative proteomics; therapeutic targets

DOI:  https://doi.org/10.1080/14789450.2023.2275681
Biomed Pharmacother. 2023 Oct 19. pii: S0753-3322(23)01528-7. [Epub ahead of print]168 115730

Copper-mediated novel cell death pathway in tumor cells and implications for innovative cancer therapies.

Xiaodan Zhang, Tao Tao, Yishu Qiu, Xiaojun Guo, Xiao Zhu, Xiaorong Zhou.

  Previous investigations have unraveled an array of cellular demise modalities, encompassing apoptosis, necrosis, pyroptosis, iron death, and several others. These diverse pathways of cell death have been harnessed as therapeutic strategies for eradicating tumor cells. Recent scientific inquiries have unveiled a novel mode of cell death, namely copper death, which is contingent upon intracellular copper levels. Diverging from conventional cell death mechanisms, copper death exhibits a heightened reliance on mitochondrial respiration, specifically the tricarboxylic acid (TCA) cycle. Tumor cells exhibit distinctive metabolic profiles and an elevated copper content compared to their normal counterparts. The emergence of copper death presents a tantalizing prospect for targeted therapies in the realm of cancer treatment. Thus, the primary objective of this review is to introduce the proteins and intricate mechanisms underlying copper death, while comprehensively summarizing the extensive body of knowledge concerning its ramifications across diverse tumor types. The insights garnered from this comprehensive synthesis will serve as an invaluable reference for driving the development of tailor-made therapeutic interventions for tumors.

Keywords:  Cellular demise modalities; Copper death; Mitochondrial respiration; Tailored therapeutic interventions; Therapeutic strategies; Tumor cell metabolism

DOI:  https://doi.org/10.1016/j.biopha.2023.115730
Nutrients. 2023 Oct 11. pii: 4329. [Epub ahead of print]15(20):

Integration with Transcriptomic and Metabolomic Analyses Reveals the In Vitro Cytotoxic Mechanisms of Chinese Poplar Propolis by Triggering the Glucose Metabolism in Human Hepatocellular Carcinoma Cells.

Yuyang Guo, Zhengxin Liu, Qian Wu, Zongze Li, Jialin Yang, Hongzhuan Xuan.

  Natural products serve as a valuable reservoir of anticancer agents. Chinese poplar propolis (CP) has exhibited remarkable antitumor activities, yet its precise mechanisms of action remain elusive. This study aims to elucidate the in vitro cytotoxic mechanisms of CP in human hepatocellular carcinoma cells (HepG2) through comprehensive transcriptomic and metabolomic analyses. Our evidence suggested that CP possesses a great potential to inhibit the proliferation of HepG2 cells by targeting the glucose metabolism. Notably, CP exhibited a dose- and time-dependent reduction in the viability of HepG2 cells. Transcriptome sequencing unveiled significant alterations in the cellular metabolism, particularly within glucose metabolism pathways. CP effectively restrained glucose consumption and lactic acid production. Moreover, the CP treatment led to a substantial decrease in the mRNA expression levels of key glucose transporters (GLUT1 and GLUT3) and glycolytic enzymes (LDHA, HK2, PKM2, and PFK). Correspondingly, CP suppressed some key protein levels. Cellular metabolomic analysis demonstrated a marked reduction in intermediary products of glucose metabolism, specifically fructose 1,6-bisphosphate and acetyl-CoA, following CP administration. Finally, key compounds in CP were screened, and apigenin, pinobanksin, pinocembrin, and galangin were identified as potential active agents against glycolysis. It indicates that the effectiveness of propolis in inhibiting liver cancer is the result of the combined action of several components. These findings underscore the potential therapeutic value of propolis in the treatment of liver cancer by targeting glycolytic pathways.

Keywords:  Chinese poplar propolis; cell metabolism; hepatocellular carcinoma cells; metabolomics; transcriptome sequencing

DOI:  https://doi.org/10.3390/nu15204329
Methods Protoc. 2023 Oct 04. pii: 94. [Epub ahead of print]6(5):

A Simple and Fast Method for the Formation and Downstream Processing of Cancer-Cell-Derived 3D Spheroids: An Example Using Nicotine-Treated A549 Lung Cancer 3D Spheres.

Irida Papapostolou, Florian Bochen, Christine Peinelt, Maria Constanza Maldifassi.

  Although 2D in vitro cancer cell cultures have been used for decades as a first line-of-research tool to investigate antitumoral drugs and treatments, their use presents many drawbacks, including the poor resemblance of such cultures to the characteristics of in vivo tumors. To mitigate these drawbacks, 3D culture models have emerged as a more representative alternative. Cancer cells cultured as 3D structures have the advantage of resembling solid tumors in their architecture and in their resistance to chemotherapeutic drugs, in part because of restrained drug penetration. Additionally, these 3D structures create a more physiological environment for the study of immune cell invasion and migration, comparable to solid tumors. In this paper, we describe a fast and cost-effective step-by-step protocol for the generation of 3D spheres using ultra-low-attachment (ULA) multiwell plates, which can be incorporated into the normal workflow of any laboratory. Using this protocol, spheroids of different human cancer cell lines can be obtained and can then be characterized on the basis of their morphology, viability, and expression of specific markers.

Keywords:  3D cell culture; cancer cells; low-attachment surface; nicotine; nicotinic acetylcholine receptors; spheroids; three-dimensional cell culture

DOI:  https://doi.org/10.3390/mps6050094
bioRxiv. 2023 Oct 03. pii: 2023.10.02.560369. [Epub ahead of print]

Controlling pericellular oxygen tension in cell culture reveals distinct breast cancer responses to low oxygen tensions.

Zachary J Rogers, Thibault Colombani, Saad Khan, Khushbu Bhatt, Alexandra Nukovic, Guanyu Zhou, Benjamin M Woolston, Cormac T Taylor, Daniele M Gilkes, Nikolai Slavov, Sidi A Bencherif.

Oxygen (O 2 ) tension plays a key role in tissue function and pathophysiology. O 2 -controlled cell culture, in which the O 2 concentration in an incubator's gas phase is controlled, is an indispensable tool to study the role of O 2 in vivo . For this technique, it is presumed that the incubator setpoint is equal to the O 2 tension that cells experience ( i.e. , pericellular O 2 ). We discovered that physioxic (5% O 2 ) and hypoxic (1% O 2 ) setpoints regularly induce anoxic (0.0% O 2 ) pericellular tensions in both adherent and suspension cell cultures. Electron transport chain inhibition ablates this effect, indicating that cellular O 2 consumption is the driving factor. RNA-seq revealed that primary human hepatocytes cultured in physioxia experience ischemia-reperfusion injury due to anoxic exposure followed by rapid reoxygenation. To better understand the relationship between incubator gas phase and pericellular O 2 tensions, we developed a reaction-diffusion model that predicts pericellular O 2 tension a priori . This model revealed that the effect of cellular O 2 consumption is greatest in smaller volume culture vessels ( e.g., 96-well plate). By controlling pericellular O 2 tension in cell culture, we discovered that MCF7 cells have stronger glycolytic and glutamine metabolism responses in anoxia vs. hypoxia. MCF7 also expressed higher levels of HIF2A , CD73 , NDUFA4L2 , etc. and lower levels of HIF1A , CA9 , VEGFA, etc. in response to hypoxia vs. anoxia. Proteomics revealed that 4T1 cells had an upregulated epithelial-to-mesenchymal transition (EMT) response and downregulated reactive oxygen species (ROS) management, glycolysis, and fatty acid metabolism pathways in hypoxia vs. anoxia. Collectively, these results reveal that breast cancer cells respond non-monotonically to low O 2 , suggesting that anoxic cell culture is not suitable to model hypoxia. We demonstrate that controlling atmospheric O 2 tension in cell culture incubators is insufficient to control O 2 in cell culture and introduce the concept of pericellular O 2 -controlled cell culture .

DOI: https://doi.org/10.1101/2023.10.02.560369
Nat Chem Biol. 2023 Oct 26.

A genetically encoded tool to increase cellular NADH/NAD+ ratio in living cells.

Xingxiu Pan, Mina L Heacock, Evana N Abdulaziz, Sara Violante, Austin L Zuckerman, Nirajan Shrestha, Canglin Yao, Russell P Goodman, Justin R Cross, Valentin Cracan.

Impaired redox metabolism is a key contributor to the etiology of many diseases, including primary mitochondrial disorders, cancer, neurodegeneration and aging. However, mechanistic studies of redox imbalance remain challenging due to limited strategies that can perturb redox metabolism in various cellular or organismal backgrounds. Most studies involving impaired redox metabolism have focused on oxidative stress; consequently, less is known about the settings where there is an overabundance of NADH reducing equivalents, termed reductive stress. Here we introduce a soluble transhydrogenase from Escherichia coli (EcSTH) as a novel genetically encoded tool to promote reductive stress in living cells. When expressed in mammalian cells, EcSTH, and a mitochondrially targeted version (mitoEcSTH), robustly elevated the NADH/NAD+ ratio in a compartment-specific manner. Using this tool, we determined that metabolic and transcriptomic signatures of the NADH reductive stress are cellular background specific. Collectively, our novel genetically encoded tool represents an orthogonal strategy to promote reductive stress.

DOI: https://doi.org/10.1038/s41589-023-01460-w
bioRxiv. 2023 Oct 10. pii: 2023.10.08.561453. [Epub ahead of print]

Adaptation to volumetric compression drives hepatoblastoma cells to an apoptosis-resistant and invasive phenotype.

Xiangyu Gong, Noriyoshi Ogino, M Fatima Leite, Zehua Chen, Ryan Nguyen, Raymond Liu, Emma Kruglov, Kaitlin Flores, Aiden Cabral, Gabriel M M Mendes, Barbara E Ehrlich, Michael Mak.

Liver cancer involves tumor cells rapidly growing within a packed tissue environment. Patient tumor tissues reveal densely packed and deformed cells, especially at tumor boundaries, indicative of physical crowding and compression. It is not well understood how these physical signals modulate tumor evolution and therapeutic susceptibility. Here we investigate the impact of volumetric compression on liver cancer (HepG2) behavior. We find that conditioning cells under a highly compressed state leads to major transcriptional reprogramming, notably the loss of hepatic markers, the epithelial-to-mesenchymal transition (EMT)-like changes, and altered calcium signaling-related gene expression, over the course of several days. Biophysically, compressed cells exhibit increased Rac1-mediated cell spreading and cell-extracellular matrix interactions, cytoskeletal reorganization, increased YAP and β-catenin nuclear translocation, and dysfunction in cytoplasmic and mitochondrial calcium signaling. Furthermore, compressed cells are resistant to chemotherapeutics and desensitized to apoptosis signaling. Apoptosis sensitivity can be rescued by stimulated calcium signaling. Our study demonstrates that volumetric compression is a key microenvironmental factor that drives tumor evolution in multiple pathological directions and highlights potential countermeasures to re-sensitize therapy-resistant cells.
Significance statement: Compression can arise as cancer cells grow and navigate within the dense solid tumor microenvironment. It is unclear how compression mediates critical programs that drive tumor progression and therapeutic complications. Here, we take an integrative approach in investigating the impact of compression on liver cancer. We identify and characterize compressed subdomains within patient tumor tissues. Furthermore, using in vitro systems, we induce volumetric compression (primarily via osmotic pressure but also via mechanical force) on liver cancer cells and demonstrate significant molecular and biophysical changes in cell states, including in function, cytoskeletal signaling, proliferation, invasion, and chemoresistance. Importantly, our results show that compressed cells have impaired calcium signaling and acquire resistance to apoptosis, which can be countered via calcium mobilization.

DOI: https://doi.org/10.1101/2023.10.08.561453
Front Microbiol. 2023 ;14 1270487

Exploring cell cycle-mediated regulations of glycolysis in budding yeast.

Yanfei Zhang, Matteo Barberis.

  Coordination of cell cycle with metabolism exists in all cell types that grow by division. It serves to build a new cell, (i) fueling building blocks for the synthesis of proteins, nucleic acids, and membranes, and (ii) producing energy through glycolysis. Cyclin-dependent kinases (Cdks) play an essential role in this coordination, thereby in the regulation of cell division. Cdks are functional homologs across eukaryotes and are the engines that drive cell cycle events and the clocks that time them. Their function is counteracted by stoichiometric inhibitors; specifically, inhibitors of cyclin-cyclin dependent kinase (cyclin/Cdk) complexes allow for their activity at specific times. Here, we provide a new perspective about the yet unknown cell cycle mechanisms impacting on metabolism. We first investigated the effect of the mitotic cyclin/Cdk1 complex Cyclin B/Cdk1-functional homolog in mammalian cells of the budding yeast Clb2/Cdk1-on yeast metabolic enzymes of, or related to, the glycolysis pathway. Six glycolytic enzymes (Glk1, Hxk2, Pgi1, Fba1, Tdh1, and Pgk1) were subjected to in vitro Cdk-mediated phosphorylation assays. Glucose-6-phosphate dehydrogenase (Zwf1), the first enzyme in the pentose phosphate pathway that is important for NADPH production, and 6-phospho-fructo-2-kinase (Pfk27), which catalyzes fructose-2,6-bisphosphate synthesis, a key regulator of glycolysis, were also included in the study. We found that, among these metabolic enzymes, Fba1 and Pgk1 may be phosphorylated by Cdk1, in addition to the known Cdk1-mediated phosphorylation of Gph1. We then investigated the possible effect of Sic1, stoichiometric inhibitor of mitotic cyclin/Cdk1 complexes in budding yeast, on the activities of three most relevant glycolytic enzymes: Hxk2, Glk1, and Tdh1. We found that Sic1 may have a negative effect on Hxk2. Altogether, we reveal possible new routes, to be further explored, through which cell cycle may regulate cellular metabolism. Because of the functional homology of cyclin/Cdk complexes and their stoichiometric inhibitors across evolution, our findings may be relevant for the regulation of cell division in eukaryotes.

Keywords:  Sic1; cell cycle; cyclin B/Cdk1; cyclin-dependent kinase; cyclin-dependent kinase inhibitor; glycolysis; metabolic enzymes; metabolism

DOI:  https://doi.org/10.3389/fmicb.2023.1270487
bioRxiv. 2023 Oct 11. pii: 2023.10.09.561530. [Epub ahead of print]

ASCT2 is the primary serine transporter in cancer cells.

Kelly O Conger, Christopher Chidley, Mete Emir Ozgurses, Huiping Zhao, Yumi Kim, Svetlana E Semina, Philippa Burns, Vipin Rawat, Ryan Sheldon, Issam Ben-Sahra, Jonna Frasor, Peter K Sorger, Gina M DeNicola, Jonathan L Coloff.

The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo , others are auxotrophic for serine and therefore reliant on the uptake of exogenous serine. Importantly, however, the transporter(s) that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (coded for by the gene SLC1A5 ) as the primary serine transporter in cancer cells. ASCT2 is well-known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that ERα promotes serine uptake by directly activating SLC1A5 transcription. Together, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target in serine metabolism.

DOI: https://doi.org/10.1101/2023.10.09.561530
J Neurochem. 2023 Oct 26.

Diet-induced diabetes is associated with lower hippocampal glycogen and reduced glycogenolysis following local exogenous insulin.

Ewan C McNay.

  Brain fuel (specifically, glucose) supply and metabolism are well-established to be limiting factors for cognitive performance, with the largest body of data being for hippocampally mediated tasks. Consistent with this, disease states such as Alzheimer's disease and insulin-resistant diabetes, that impair cognitive metabolism, impair cognition with this being shown again most prominently for hippocampally mediated processes. In addition to glucose supplied from the blood, brain oxidative metabolism can use local glycogen stores (within astrocytes) as a fuel source via conversion to lactate; both lactate and glycogen have been shown to be important contributors to regulation of cognitive metabolism. Insulin has been shown to be a key regulator of hippocampal cognitive and metabolic processes; in the periphery, insulin facilitates glycogen synthesis and storage, but the impact on brain glycogen is unclear. Furthermore, the impact of diet-induced diabetes on hippocampal glycogen levels and/or metabolism is unknown. Here, we show that in rats with high-fat diet-induced diabetes, hippocampal glycogen is reduced and is less responsive to acute intrahippocampal administration of insulin, which significantly reduces glycogen in the hippocampi of control animals: Our data suggest that impaired fuel availability from glycogen may be a contributing factor to the cognitive impairment seen in disease states that include central insulin resistance.

Keywords:  AD; T2DM; glycogen; hippocampus; insulin

DOI:  https://doi.org/10.1111/jnc.16001
World J Surg Oncol. 2023 Oct 26. 21(1): 334

Current knowledge and potential intervention of hexosamine biosynthesis pathway in lung cancer.

Yi Zou, Zongkai Liu, Wenjia Liu, Zhaidong Liu.

  Lung cancer is a highly prevalent malignancy characterized by significant metabolic alterations. Understanding the metabolic rewiring in lung cancer is crucial for the development of effective therapeutic strategies. The hexosamine biosynthesis pathway (HBP) is a metabolic pathway that plays a vital role in cellular metabolism and has been implicated in various cancers, including lung cancer. Abnormal activation of HBP is involved in the proliferation, progression, metastasis, and drug resistance of tumor cells. In this review, we will discuss the function and regulation of metabolic enzymes related to HBP in lung cancer. Furthermore, the implications of targeting the HBP for lung cancer treatment are also discussed, along with the challenges and future directions in this field. This review provides a comprehensive understanding of the role and intervention of HBP in lung cancer. Future research focusing on the HBP in lung cancer is essential to uncover novel treatment strategies and improve patient outcomes.

Keywords:  Hexosamine biosynthesis pathway; Intervention; Lung cancer; Metabolism

DOI:  https://doi.org/10.1186/s12957-023-03226-z
Cancers (Basel). 2023 Oct 20. pii: 5082. [Epub ahead of print]15(20):

A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer.

Xiao-Dan Lyu, Yang Liu, Jia Wang, Yuan-Cheng Wei, Yi Han, Xue Li, Qian Zhang, Zheng-Rui Liu, Zheng-Zheng Li, Jing-Wei Jiang, Hao-Lin Hu, Sheng-Tao Yuan, Li Sun.

   BACKGROUND: The microtubule protein inhibitor C118P shows excellent anti-breast cancer effects. However, the potential targets and mechanisms of C118P in breast cancer remain unknown.
METHODS: Real-time cellular analysis (RTCA) was used to detect cell viability. Apoptosis and the cell cycle were detected by flow cytometry. Computer docking simulations, surface plasmon resonance (SPR) technology, and microscale thermophoresis (MST) were conducted to study the interaction between C118P and alanine-serine-cysteine transporter 2 (ASCT2). Seahorse XF technology was used to measure the basal oxygen consumption rate (OCR). The effect of C118P in the adipose microenvironment was explored using a co-culture model of adipocytes and breast cancer cells and mouse cytokine chip.
RESULTS: C118P inhibited proliferation, potentiated apoptosis, and induced G2/M cell cycle arrest in breast cancer cells. Notably, ASCT2 was validated as a C118P target through reverse docking, SPR, and MST. C118P suppressed glutamine metabolism and mediated autophagy via ASCT2. Similar results were obtained in the adipocyte-breast cancer microenvironment. Adipose-derived interleukin-6 (IL-6) promoted the proliferation of breast cancer cells by enhancing glutamine metabolism via ASCT2. C118P inhibited the upregulation of ASCT2 by inhibiting the effect of IL-6 in co-cultures.
CONCLUSION: C118P exerts an antitumour effect against breast cancer via the glutamine transporter ASCT2.

Keywords:  ASCT2; C118P; breast neoplasms; cell proliferation; interleukin-6

DOI:  https://doi.org/10.3390/cancers15205082
Biomed Pharmacother. 2023 Oct 19. pii: S0753-3322(23)01457-9. [Epub ahead of print]168 115659

Integration of metabolomics and transcriptomics reveals metformin suppresses thyroid cancer progression via inhibiting glycolysis and restraining DNA replication.

Jielin Ouyang, Yang Feng, Yiyuan Zhang, Yarong Liu, Shutong Li, Jingjing Wang, Lihong Tan, Lianhong Zou.

  The anti-tumoral effects of metformin have been widely studied in several types of cancer, including thyroid cancer; however, the underlying molecular mechanisms remain poorly understood. As an oral hypoglycemic drug, metformin facilitates glucose catabolism and disrupts metabolic homeostasis. Metabolic reprogramming, particularly cellular glucose metabolism, is an important characteristic of malignant tumors. This study aimed to explore the therapeutic effects of metformin in thyroid cancer and the underlying metabolic mechanism. In the present study, it was shown that metformin reduced cell viability, invasion, migration, and EMT, and induced apoptosis and cell cycle G1 phase arrest in thyroid cancer. Transcriptome analysis demonstrated that the differentially expressed genes induced by metformin were involved in several signaling pathways including apoptosis singling pathways, TGF-β signaling, and cell cycle regulation in human thyroid cancer cell lines. In addition, the helicase activity of the CDC45-MCM2-7-GINS complex and DNA replication related genes such as RPA2, RAD51, and PCNA were downregulated in metformin-treated thyroid cancer cells. Moreover, metabolomics analysis showed that metformin-induced significant alterations in metabolic pathways such as glutathione metabolism and polyamine synthesis. Integrative analysis of transcriptomes and metabolomics revealed that metformin suppressed glycolysis by downregulating the key glycolytic enzymes LDHA and PKM2 and upregulating IDH1 expression in thyroid cancer. Furthermore, the anti-tumor role of metformin in thyroid cancer in vivo was shown. Together these results show that metformin plays an anti-tumor role by inhibiting glycolysis and restraining DNA replication in thyroid cancer.

Keywords:  Anti-tumor; Metabolomics; Metformin; Thyroid cancer; Transcriptomics

DOI:  https://doi.org/10.1016/j.biopha.2023.115659
Sci Rep. 2023 Oct 26. 13(1): 18380

Comparative analysis between 2D and 3D colorectal cancer culture models for insights into cellular morphological and transcriptomic variations.

Zaid Nsaif Abbas, Ali Z Al-Saffar, Saba Mahdi Jasim, Ghassan M Sulaiman.

Drug development is a time-consuming and expensive process, given the low success rate of clinical trials. Now, anticancer drug developments have shifted to three-dimensional (3D) models which are more likely to mimic tumor behavior compared to traditional two-dimensional (2D) cultures. A comparative study among different aspects was conducted between 2D and 3D cultures using colorectal cancer (CRC) cell lines, in addition, Formalin-Fixed Paraffin-Embedded (FFPE) block samples of patients with CRC were used for evaluation. Compared to the 2D culture, cells grown in 3D displayed significant (p < 0.01) differences in the pattern of cell proliferation over time, cell death phase profile, expression of tumorgenicity-related genes, and responsiveness to 5-fluorouracil, cisplatin, and doxorubicin. Epigenetically, 3D cultures and FFPE shared the same methylation pattern and microRNA expression, while 2D cells showed elevation in methylation rate and altered microRNA expression. Lastly, transcriptomic study depending on RNA sequencing and thorough bioinformatic analyses showed significant (p-adj < 0.05) dissimilarity in gene expression profile between 2D and 3D cultures involving thousands of genes (up/down-regulated) of multiple pathways for each cell line. Taken together, the study provides insights into variations in cellular morphologies between cells cultured in 2D and 3D models.

DOI: https://doi.org/10.1038/s41598-023-45144-w
Redox Biol. 2023 Oct 17. pii: S2213-2317(23)00333-6. [Epub ahead of print]67 102932

Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.

Gerardo G Piroli, Allison M Manuel, Richard S McCain, Holland H Smith, Oliver Ozohanics, Sara Mellid, J Hunter Cox, William E Cotham, Michael D Walla, Alberto Cascón, Attila Ambrus, Norma Frizzell.

  The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the α-ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the affected regions of the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the existing oxidative phosphorylation (OXPHOS) ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.

Keywords:  Alpha-ketoglutarate dehydrogenase; Complex I; Fumarate; Leigh syndrome; Protein succination; Substrate level phosphorylation

DOI:  https://doi.org/10.1016/j.redox.2023.102932
bioRxiv. 2023 Oct 03. pii: 2023.10.02.560330. [Epub ahead of print]

Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium.

Anagha Inguva Sheth, Krysta Engel, Hunter Tolison, Mark J Althoff, Maria L Amaya, Anna Krug, Tracy Young, Shanshan Pei, Sweta B Patel, Mohammad Minhajuddin, Amanda Winters, Regan Miller, Ian Shelton, Jonathan St-Germain, Tianyi Ling, Courtney Jones, Brian Raught, Austin Gillen, Monica Ransom, Sarah Staggs, Clayton A Smith, Daniel A Pollyea, Brett M Stevens, Craig T Jordan.

We previously reported that acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL2, creating a therapeutic opportunity to target LSCs using the BCL2 inhibitor drug venetoclax. While venetoclax-based regimens have indeed shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence mechanisms that dictate venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e., OXPHOS) status with relatively high steady-state levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake sharply reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in the biology of LSCs and provide a therapeutic avenue for clinical management of venetoclax resistance.
Significance: We identify increased utilization of mitochondrial calcium as distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy.

DOI: https://doi.org/10.1101/2023.10.02.560330
Development. 2023 Oct 15. pii: dev201610. [Epub ahead of print]150(20):

Beyond energy and growth: the role of metabolism in developmental signaling, cell behavior and diapause.

Trevor S Tippetts, Matthew H Sieber, Ashley Solmonson.

  Metabolism is crucial for development through supporting cell growth, energy production, establishing cell identity, developmental signaling and pattern formation. In many model systems, development occurs alongside metabolic transitions as cells differentiate and specialize in metabolism that supports new functions. Some cells exhibit metabolic flexibility to circumvent mutations or aberrant signaling, whereas other cell types require specific nutrients for developmental progress. Metabolic gradients and protein modifications enable pattern formation and cell communication. On an organism level, inadequate nutrients or stress can limit germ cell maturation, implantation and maturity through diapause, which slows metabolic activities until embryonic activation under improved environmental conditions.

Keywords:  Diapause; Embryogenesis; Metabolism; Signaling

DOI:  https://doi.org/10.1242/dev.201610
Nutrients. 2023 Oct 18. pii: 4427. [Epub ahead of print]15(20):

Ketogenic Diet Exacerbates L-Arginine-Induced Acute Pancreatitis and Reveals the Therapeutic Potential of Butyrate.

He Xia, Jing Guo, Jian Shen, Shiman Jiang, Shengyi Han, Lanjuan Li.

  The ketogenic diet (KD) has emerged as a popular weight-loss regimen in recent years. However, it has been confirmed to elicit a mild inflammatory response in the intestinal epithelium and exacerbate various digestive disorders. The severity of acute pancreatitis (AP) is closely associated with the permeability of the intestinal epithelium and gut microbiota, yet the impact of KD on acute pancreatitis remains unclear. In this study, we induced acute pancreatitis using L-arginine in mice fed with KD. The consumption of KD resulted in an elevation of lipopolysaccharide-binding protein (LBP), accompanied by upregulated cytokines (IL-1a, IL-5, IL-12, MIP-1a, and Rantes) and dysfunction of the intestinal barrier both in control and AP groups. The bloom of Lachnospirales and Erysipelotrichales was observed as a specific profile of gut microbiota in KD-fed mice with AP, along with downregulation of carbohydrate metabolism and depletion of short-chain fatty acids (SCFAs). Antibiotic decontamination reduced the cytokine storm and tissue necrosis but did not significantly improve the integrity of the intestinal barrier in KD-fed mice with AP. The overgrowth of Mycoplasmatales in feces and Enterobacterales in colonic tissue appears to explain the limitation of antibiotic treatment to aggravate acute pancreatitis. Butyrate supplementation attenuated the depletion of SCFAs, promoted the intestinal barrier, and reduced the necrotic area in AP mice. The bloom of Bacteroidales and the correlated increase in tryptophan metabolism explain the therapeutic potential of butyrate supplements for acute pancreatitis. In conclusion, our findings suggest that the ketogenic diet exacerbates acute pancreatitis through its impact on the gut microbiota and subsequent disruption of the intestinal barrier, while butyrate supplementation reverses this effect.

Keywords:  L-arginine; acute pancreatitis; butyrate; ketogenic diet

DOI:  https://doi.org/10.3390/nu15204427
Sci Rep. 2023 Oct 27. 13(1): 18448

Ketogenic diet influence on the elemental homeostasis of internal organs is gender dependent.

Kamil Kawon, Marzena Rugiel, Zuzanna Setkowicz, Katarzyna Matusiak, Aldona Kubala-Kukus, Ilona Stabrawa, Karol Szary, Zuzanna Rauk, Joanna Chwiej.

The ketogenic diet (KD) is a low-carbohydrate and high-fat diet that gains increasing popularity in the treatment of numerous diseases, including epilepsy, brain cancers, type 2 diabetes and various metabolic syndromes. Although KD is effective in the treatment of mentioned medical conditions, it is unfortunately not without side effects. The most frequently occurring undesired outcomes of this diet are nutrient deficiencies, the formation of kidney stones, loss of bone mineral density, increased LDL (low-density lipoprotein) cholesterol levels and hormonal disturbances. Both the diet itself and the mentioned adverse effects can influence the elemental composition and homeostasis of internal organs. Therefore, the objective of this study was to determine the elemental abnormalities that appear in the liver, kidney, and spleen of rats subjected to long-term KD treatment. The investigation was conducted separately on males and females to determine if observed changes in the elemental composition of organs are gender-dependent. To measure the concentration of P, S, K, Ca, Fe, Cu, Zn and Se in the tissues the method of the total reflection X-ray fluorescence (TXRF) was utilized. The obtained results revealed numerous elemental abnormalities in the organs of animals fed a high-fat diet. Only some of them can be explained by the differences in the composition and intake of the ketogenic and standard diets. Furthermore, in many cases, the observed anomalies differed between male and female rats.

DOI: https://doi.org/10.1038/s41598-023-45611-4
Cancer Sci. 2023 Oct 26.

Phospholipid metabolic adaptation promotes survival of IDH2 mutant acute myeloid leukemia cells.

Tatsuya Morishima, Koichi Takahashi, Desmond Wai Loon Chin, Yuxin Wang, Kenji Tokunaga, Yuichiro Arima, Masao Matsuoka, Toshio Suda, Hitoshi Takizawa.

  Genetic mutations in the isocitrate dehydrogenase (IDH) gene that result in a pathological enzymatic activity to produce oncometabolite have been detected in acute myeloid leukemia (AML) patients. While specific inhibitors that target mutant IDH enzymes and normalize intracellular oncometabolite level have been developed, refractoriness and resistance has been reported. Since acquisition of pathological enzymatic activity is accompanied by the abrogation of the crucial WT IDH enzymatic activity in IDH mutant cells, aberrant metabolism in IDH mutant cells can potentially persist even after the normalization of intracellular oncometabolite level. Comparisons of isogenic AML cell lines with and without IDH2 gene mutations revealed two mutually exclusive signalings for growth advantage of IDH2 mutant cells, STAT phosphorylation associated with intracellular oncometabolite level and phospholipid metabolic adaptation. The latter came to light after the oncometabolite normalization and increased the resistance of IDH2 mutant cells to arachidonic acid-mediated apoptosis. The release of this metabolic adaptation by FDA-approved anti-inflammatory drugs targeting the metabolism of arachidonic acid could sensitize IDH2 mutant cells to apoptosis, resulting in their eradication in vitro and in vivo. Our findings will contribute to the development of alternative therapeutic options for IDH2 mutant AML patients who do not tolerate currently available therapies.

Keywords:  acute myeloid leukemia; apoptosis; arachidonic acid; drug repositioning; phospholipid

DOI:  https://doi.org/10.1111/cas.15994