bims-medica 2023-10-22 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2023–10–22
thirty-one papers selected by
Brett Chrest, East Carolina University

Unlocking the potential of the tumor microenvironment for cancer therapy.
Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance.
Comparison of Engineered Liver 3D Models and the Role of Oxygenation for Patient-Derived Tumor Cells and Immortalized Cell Lines Cocultured with Tumor Stroma in the Detection of Hepatotoxins.
Evaluation of Mitochondrial Function on Pyruvate Dehydrogenase Complex Deficient Patient-derived Cell Lines.
Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.
Cancer Metabolism under Limiting Oxygen Conditions.
Resveratrol: biology, metabolism, and detrimental role on the tumor microenvironment of colorectal cancer.
A low-carbohydrate diet with different fatty acids' sources in the treatment of obesity: Impact on insulin resistance and adipogenesis.
Metabolic reprogramming, autophagy, and ferroptosis: Novel arsenals to overcome immunotherapy resistance in gastrointestinal cancer.
Targeting metabolic vulnerabilities to overcome resistance to therapy in acute myeloid leukemia.
Efficient single-cell oxygen consumption rate characterization based on frequency domain fluorescence lifetime imaging microscopy measurement and microfluidic platform.
The metabolic control theory: Its development and its application to mitochondrial oxidative phosphorylation.
Delineating a role for methionine metabolism in colorectal cancer.
Nucleotide metabolism in the regulation of tumor microenvironment and immune cell function.
A comprehensive overview of recent developments on the mechanisms and pathways of ferroptosis in cancer: the potential implications for therapeutic strategies in ovarian cancer.
Targeting succinylation-mediated metabolic reprogramming as a potential approach for cancer therapy.
Warburg-associated acidification represses lactic fermentation independently of lactate, contribution from real-time NMR on cell-free systems.
Metabolic control of cancer metastasis: role of amino acids at secondary organ sites.
Timosaponin AIII induces lipid peroxidation and ferroptosis by enhancing Rab7-mediated lipophagy in colorectal cancer cells.
Metabolic advantages of regulatory T cells dictated by cancer cells.
Dietary galactose increases the expression of mitochondrial OXPHOS genes and modulates the carbohydrate oxidation pathways in mouse intestinal mucosa.
CD36 maintains lipid homeostasis via selective uptake of monounsaturated fatty acids during matrix detachment and tumor progression.
Single-cell metabolic profiling reveals subgroups of primary human hepatocytes with heterogeneous responses to drug challenge.
Phenethyl isothiocyanate and dasatinib combination synergistically reduces hepatocellular carcinoma growth via cell cycle arrest and oxeiptosis.
Metabolic remodeling in astrocytes: Paving the path to brain tumor development.
Preparation of a Mesoporous Biosensor for Human Lactate Dehydrogenase for Potential Anticancer Inhibitor Screening.
M4IDP stimulates ROS elevation through inhibition of mevalonate pathway and pentose phosphate pathway to inhibit colon cancer cells.
Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer.
Unlocking the potential of organoids in cancer treatment and translational research: An application of cytologic techniques.
Stable isotope tracing reveals disturbed cellular energy and glutamate metabolism in hippocampal slices of aged male mice.
The Impact of Heterogeneous Cell Density in Hypoxic Tumors Treated with Radiotherapy.

Pathol Res Pract. 2023 Oct 04. pii: S0344-0338(23)00547-2. [Epub ahead of print]251 154846

Unlocking the potential of the tumor microenvironment for cancer therapy.

Muhammad Tufail.

  The tumor microenvironment (TME) holds a crucial role in the progression of cancer. Epithelial-derived tumors share common traits in shaping the TME. The Warburg effect is a notable phenomenon wherein tumor cells exhibit resistance to apoptosis and an increased reliance on anaerobic glycolysis for energy production. Recognizing the pivotal role of the TME in controlling tumor growth and influencing responses to chemotherapy, researchers have focused on developing potential cancer treatment strategies. A wide array of therapies, including immunotherapies, antiangiogenic agents, interventions targeting cancer-associated fibroblasts (CAF), and therapies directed at the extracellular matrix, have been under investigation and have demonstrated efficacy. Additionally, innovative techniques such as tumor tissue explants, "tumor-on-a-chip" models, and multicellular tumor spheres have been explored in laboratory research. This comprehensive review aims to provide insights into the intricate cross-talk between cancer-associated signaling pathways and the TME in cancer progression, current therapeutic approaches targeting the TME, the immune landscape within solid tumors, the role of the viral TME, and cancer cell metabolism.

Keywords:  Cancer cell metabolism; Solid tumors microenvironment; Targeting the tumor microenvironment; Tumor landscape; Tumor mechanics; Viral induced tumor microenvironment

DOI:  https://doi.org/10.1016/j.prp.2023.154846
iScience. 2023 Oct 20. 26(10): 108059

Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance.

Mohammad A Iqbal, Shumaila Siddiqui, Kirk Smith, Prithvi Singh, Bhupender Kumar, Salem Chouaib, Sriram Chandrasekaran.

  Extensive metabolic heterogeneity in breast cancers has limited the deployment of metabolic therapies. To enable patient stratification, we studied the metabolic landscape in breast cancers (∼3000 patients combined) and identified three subtypes with increasing degrees of metabolic deregulation. Subtype M1 was found to be dependent on bile-acid biosynthesis, whereas M2 showed reliance on methionine pathway, and M3 engaged fatty-acid, nucleotide, and glucose metabolism. The extent of metabolic alterations correlated strongly with tumor aggressiveness and patient outcome. This pattern was reproducible in independent datasets and using in vivo tumor metabolite data. Using machine-learning, we identified robust and generalizable signatures of metabolic subtypes in tumors and cell lines. Experimental inhibition of metabolic pathways in cell lines representing metabolic subtypes revealed subtype-specific sensitivity, therapeutically relevant drugs, and promising combination therapies. Taken together, metabolic stratification of breast cancers can thus aid in predicting patient outcome and designing precision therapies.

Keywords:  Medical informatics; cancer; computational bioinformatics

DOI:  https://doi.org/10.1016/j.isci.2023.108059
Adv Biol (Weinh). 2023 Oct 16. e2300386

Comparison of Engineered Liver 3D Models and the Role of Oxygenation for Patient-Derived Tumor Cells and Immortalized Cell Lines Cocultured with Tumor Stroma in the Detection of Hepatotoxins.

Mona Mansouri, Astha Lamichhane, Dola Das, Federico Aucejo, Hossein Tavana, Nic D Leipzig.

  In metabolically active tumors, responses of cells to drugs are heavily influenced by oxygen availability via the surrounding vasculature alongside the extracellular matrix signaling. The objective of this study is to investigate hepatotoxicity by replicating critical features of hepatocellular carcinoma (HCC). This includes replicating 3D structures, metabolic activities, and tumor-specific markers. The internal environment of spheroids comprised of cancerous human patient-derived hepatocytes using microparticles is modulated to enhance the oxygenation state and recreate cell-extracellular matrix interactions. Furthermore, the role of hepatic stellate cells in maintaining hepatocyte survival and function is explored and hepatocytes from two cellular sources (immortalized and patient-derived) to create four formulations with and without microparticles are utilized. To investigate drug-induced changes in metabolism and apoptosis in liver cells, coculture spheroids with and without microparticles are exposed to three hepatotoxic drugs. The use of microparticles increases levels of apoptotic markers in both liver models under drug treatments. This coincides with reduced levels of anti-apoptotic proteins and increased levels of pro-apoptotic proteins. Moreover, cells from different origins undergo apoptosis through distinct apoptotic pathways in response to identical drugs. This 3D microphysiological system offers a viable tool for liver cancer research to investigate mechanisms of apoptosis under different microenvironmental conditions.

Keywords:  apoptosis pathways; drug screening; modeling liver tumors; oxygenation; polymeric microparticles

DOI:  https://doi.org/10.1002/adbi.202300386
Endocr Metab Immune Disord Drug Targets. 2023 Oct 11.

Evaluation of Mitochondrial Function on Pyruvate Dehydrogenase Complex Deficient Patient-derived Cell Lines.

Hana Pavlú-Pereira, Cristina Florindo, Filipa Carvalho, Isabel Tavares de Almeida, Joao Vicente, Vanessa Morais, Isabel Rivera.

   INTRODUCTION: Pyruvate Dehydrogenase Complex (PDC) is a pivotal gatekeeper between cytosolic glycolysis and mitochondrial oxidative phosphorylation, playing important role in aerobic energy metabolism. Most PDC deficiency, cases being caused by mutations in PDHA1 encoding the α subunit of the rate-limiting E1 enzyme, which is characterized by abnormal phenotypes caused by energy deprivation at peripheral/central nervous systems and muscular tissues. This study aims to evaluate the potential therapeutic effect of arginine and thiamine in ameliorating mitochondrial function in patient-derived cultured cells.
MATERIALS AND METHODS: PDC-deficient cell lines, carrying three different PDHA1 variants, were cultured in the absence and presence of arginine and/or thiamine at therapeutical levels, 4 mM and 100 μM, respectively. Mitochondrial bioenergetics profile was evaluated using the Seahorse extracellular flux analyzer.
RESULTS: In physiological conditions, control cells presented standard values for all parameters evaluating the mitochondrial function, no differences being observed after supplementation of culture medium with therapeutic levels of arginine and/or thiamine. However, PDC-PDHA1 deficient cell lines consumed less oxygen than the control cells, but arginine and thiamine supplementation increased the basal respiration for values similar or higher than the control cell line. Moreover, arginine and thiamine treatment highlighted an inefficient oxidative phosphorylation carried out by PDC-deficient cell lines. Finally, this treatment showed an increased oxygen consumption by enzymes other than those in the respiratory chain, thus proving the dependence of these mutant cell lines on cytosolic sources for ATP production, namely glycolysis.
CONCLUSIONS: This study showed that arginine and thiamine, at therapeutical levels, increase the basal oxygen consumption rate of PDC-deficient cell lines, as well as their ATP-linked respiration. This parameter measures the capacity of the cell to meet its energetic demands and, therefore, its increase reveals a higher electron flow through the respiratory chain, which is coupled to elevated oxidative phosphorylation, thus indicating an overall increased robustness in mitochondrial- related bioenergetics.

Keywords:  arginine; energy metabolism; mitochondrial bioenergetics; pyruvate dehydrogenase complex; pyruvate dehydrogenase complex deficiency; thiamine

DOI:  https://doi.org/10.2174/0118715303280072231004082458
Cancer Metab. 2023 Oct 19. 11(1): 18

Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.

Amy K Holt, Arafath K Najumudeen, Tracey J Collard, Hao Li, Laura M Millett, Ashley J Hoskin, Danny N Legge, Eleanor M H Mortensson, Dustin J Flanagan, Nicholas Jones, Madhu Kollareddy, Penny Timms, Matthew D Hitchings, James Cronin, Owen J Sansom, Ann C Williams, Emma E Vincent.

   BACKGROUND: To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.
METHODS: We generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2-4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.
RESULTS: We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor-CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.
CONCLUSIONS: Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.

Keywords:  Aspirin; CB-839; Colorectal cancer; Glutaminase; Metabolic reprogramming; Metabolism

DOI:  https://doi.org/10.1186/s40170-023-00318-y
Cold Spring Harb Perspect Med. 2023 Oct 17. pii: a041542. [Epub ahead of print]

Cancer Metabolism under Limiting Oxygen Conditions.

Laura C Kim, Nicholas P Lesner, M Celeste Simon.

Molecular oxygen (O2) is essential for cellular bioenergetics and numerous biochemical reactions necessary for life. Solid tumors outgrow the native blood supply and diffusion limits of O2, and therefore must engage hypoxia response pathways that evolved to withstand acute periods of low O2 Hypoxia activates coordinated gene expression programs, primarily through hypoxia inducible factors (HIFs), to support survival. Many of these changes involve metabolic rewiring such as increasing glycolysis to support ATP generation while suppressing mitochondrial metabolism. Since low O2 is often coupled with nutrient stress in the tumor microenvironment, other responses to hypoxia include activation of nutrient uptake pathways, metabolite scavenging, and regulation of stress and growth signaling cascades. Continued development of models that better recapitulate tumors and their microenvironments will lead to greater understanding of oxygen-dependent metabolic reprogramming and lead to more effective cancer therapies.

DOI: https://doi.org/10.1101/cshperspect.a041542
Nutr Rev. 2023 Oct 20. pii: nuad133. [Epub ahead of print]

Resveratrol: biology, metabolism, and detrimental role on the tumor microenvironment of colorectal cancer.

Begum Dariya, Bala Prabhakar Girish, Neha Merchant, Mundla Srilatha, Ganji Purnachandra Nagaraju.

  A substantial increase in colorectal cancer (CRC)-associated fatalities can be attributed to tumor recurrence and multidrug resistance. Traditional treatment options, including radio- and chemotherapy, also exhibit adverse side effects. Ancient treatment strategies that include phytochemicals like resveratrol are now widely encouraged as an alternative therapeutic option. Resveratrol is the natural polyphenolic stilbene in vegetables and fruits like grapes and apples. It inhibits CRC progression via targeting dysregulated cancer-promoting pathways, including PI3K/Akt/Kras, targeting transcription factors like NF-κB and STAT3, and an immunosuppressive tumor microenvironment. In addition, combination therapies for cancer include resveratrol as an adjuvant to decrease multidrug resistance that develops in CRC cells. The current review discusses the biology of resveratrol and explores different mechanisms of action of resveratrol in inhibiting CRC progression. Further, the detrimental role of resveratrol on the immunosuppressive tumor microenvironment of CRC has been discussed. This review illustrates clinical trials on resveratrol in different cancers, including resveratrol analogs, and their efficiency in promoting CRC inhibition.

Keywords:  analogs; colorectal cancer; multidrug resistance; resveratrol; tumor microenvironment

DOI:  https://doi.org/10.1093/nutrit/nuad133
Clin Nutr. 2023 Oct 10. pii: S0261-5614(23)00313-8. [Epub ahead of print]42(12): 2381-2394

A low-carbohydrate diet with different fatty acids' sources in the treatment of obesity: Impact on insulin resistance and adipogenesis.

Aline B Santamarina, Laís V Mennitti, Esther A de Souza, Leonardo M de Souza Mesquita, Isaú H Noronha, José Ronnie C Vasconcelos, Carla M Prado, Luciana P Pisani.

   BACKGROUND: The search for nutritional intervention strategies against obesity has grown, highlighting the low-carbohydrate diet model. However, little is known about the impact of the quality of fatty acids consumed in this diet. Thus, we aim to investigate the influence of fatty acid quality on dietary strategy on obesity.
METHODS: Male Swiss mice were diet-induced to obesity. Afterward, mice consume a low-carb diet with different types of fat: saturated, polyunsaturated ω-3, ω-6, and monounsaturated ω-9 fatty acids. Weight gain and food consumption were monitored weekly. An oral glucose tolerance test was performed and blood and tissue samples were collected for analysis of insulin resistance markers. Protein expression of insulin signaling pathway molecules, lipid metabolism, mitochondrial function, macrophage polarization, and cytokine production were analyzed.
RESULTS: The high-fat diet was able to induce obesity and glucose intolerance. The switch to a low-carbohydrate dietary pattern reversed the glucose intolerance, with better results in the ω-3 and ω-9 groups. After the low-carbohydrate diet, groups ω-3 and ω-9 presented improved fasting serum glucose, insulin, and HOMA indexes. The low-carbohydrate diet also increased the activity of insulin pathway proteins such as IR, IRS1, and AKT. Furthermore, the ω-3 diet group showed greater activity of mitochondrial complexes and AMPK signaling pathway proteins. The ω-6 and ω-9 -rich diet induced M2-type macrophage polarization, as well as cytokine production modulation by the low-carbohydrate diet in the ω-3 and ω-9 groups.
CONCLUSIONS: Consuming a low-carbohydrate diet pattern promotes weight loss and improves glucose intolerance in obesity. Also, the quality of lipids has a direct influence, demonstrating that the consumption of ω-3 polyunsaturated and ω-9 monounsaturated lipids can lead to more favorable outcomes for the improvement of glucose intolerance, lipid metabolism, and anti-inflammatory effects.

Keywords:  Fatty acids; Inflammation; Insulin resistance; Lipid metabolism; Low-carbohydrate diet; Obesity

DOI:  https://doi.org/10.1016/j.clnu.2023.09.024
Cancer Med. 2023 Oct 20.

Metabolic reprogramming, autophagy, and ferroptosis: Novel arsenals to overcome immunotherapy resistance in gastrointestinal cancer.

Xiangwen Wang, Liwen Zhou, Hongpeng Wang, Wei Chen, Lei Jiang, Guangtao Ming, Jun Wang.

   BACKGROUND: Gastrointestinal cancer poses a serious health threat owing to its high morbidity and mortality. Although immune checkpoint blockade (ICB) therapies have achieved meaningful success in most solid tumors, the improvement in survival in gastrointestinal cancers is modest, owing to sparse immune response and widespread resistance. Metabolic reprogramming, autophagy, and ferroptosis are key regulators of tumor progression.
METHODS: A literature review was conducted to investigate the role of the metabolic reprogramming, autophagy, and ferroptosis in immunotherapy resistance of gastrointestinal cancer.
RESULTS: Metabolic reprogramming, autophagy, and ferroptosis play pivotal roles in regulating the survival, differentiation, and function of immune cells within the tumor microenvironment. These processes redefine the nutrient allocation blueprint between cancer cells and immune cells, facilitating tumor immune evasion, which critically impacts the therapeutic efficacy of immunotherapy for gastrointestinal cancers. Additionally, there exists profound crosstalk among metabolic reprogramming, autophagy, and ferroptosis. These interactions are paramount in anti-tumor immunity, further promoting the formation of an immunosuppressive microenvironment and resistance to immunotherapy.
CONCLUSIONS: Consequently, it is imperative to conduct comprehensive research on the roles of metabolic reprogramming, autophagy, and ferroptosis in the resistance of gastrointestinal tumor immunotherapy. This understanding will illuminate the clinical potential of targeting these pathways and their regulatory mechanisms to overcome immunotherapy resistance in gastrointestinal cancers.

Keywords:  autophagy; ferroptosis; gastrointestinal cancer; immunotherapy resistance; metabolic reprogramming

DOI:  https://doi.org/10.1002/cam4.6623
Cancer Drug Resist. 2023 ;6(3): 567-589

Targeting metabolic vulnerabilities to overcome resistance to therapy in acute myeloid leukemia.

Priyanka Sharma, Gautam Borthakur.

  Malignant hematopoietic cells gain metabolic plasticity, reorganize anabolic mechanisms to improve anabolic output and prevent oxidative damage, and bypass cell cycle checkpoints, eventually outcompeting normal hematopoietic cells. Current therapeutic strategies of acute myeloid leukemia (AML) are based on prognostic stratification that includes mutation profile as the closest surrogate to disease biology. Clinical efficacy of targeted therapies, e.g., agents targeting mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1 or 2, are mostly limited to the presence of relevant mutations. Recent studies have not only demonstrated that specific mutations in AML create metabolic vulnerabilities but also highlighted the efficacy of targeting metabolic vulnerabilities in combination with inhibitors of these mutations. Therefore, delineating the functional relationships between genetic stratification, metabolic dependencies, and response to specific inhibitors of these vulnerabilities is crucial for identifying more effective therapeutic regimens, understanding resistance mechanisms, and identifying early response markers, ultimately improving the likelihood of cure. In addition, metabolic changes occurring in the tumor microenvironment have also been reported as therapeutic targets. The metabolic profiles of leukemia stem cells (LSCs) differ, and relapsed/refractory LSCs switch to alternative metabolic pathways, fueling oxidative phosphorylation (OXPHOS), rendering them therapeutically resistant. In this review, we discuss the role of cancer metabolic pathways that contribute to the metabolic plasticity of AML and confer resistance to standard therapy; we also highlight the latest promising developments in the field in translating these important findings to the clinic and discuss the tumor microenvironment that supports metabolic plasticity and interplay with AML cells.

Keywords:  DHODH; IDH; OXPHOS; leukemia stem cells; mesenchymal stromal cells

DOI:  https://doi.org/10.20517/cdr.2023.12
Biomicrofluidics. 2023 Sep;17(5): 054105

Efficient single-cell oxygen consumption rate characterization based on frequency domain fluorescence lifetime imaging microscopy measurement and microfluidic platform.

Santhosh Kannan, Ping-Liang Ko, Hsiao-Mei Wu, Yi-Chung Tung.

Cell metabolism is critical in regulating normal cell functions to maintain energy homeostasis. In order to monitor cell metabolism, the oxygen consumption rate (OCR) of cells has been characterized as an important factor. In conventional cell analysis, the cells are characterized in bulk due to technical limitations. However, the heterogeneity between the cells cannot be identified. Therefore, single-cell analysis has been proposed to reveal cellular functions and their heterogeneity. In this research, an approach integrating a microfluidic device and widefield frequency domain fluorescence imaging lifetime microscopy (FD-FLIM) for single-cell OCR characterization in an efficient manner is developed. The microfluidic device provides an efficient platform to trap and isolate single cells in microwells with the buffer saline containing an oxygen-sensitive phosphorescent dye. The oxygen tension variation within the microwells can be efficiently estimated by measuring the fluorescence lifetime change using the FD-FLIM, and the OCR values of the single cells can then be calculated. In the experiments, breast cancer (MCF-7) cells are exploited for the OCR measurement. The results demonstrate the functionality of the developed approach and show the heterogeneity among the cells. The developed approach possesses great potential to advance cellular metabolism studies with single-cell resolution.

DOI: https://doi.org/10.1063/5.0161752
Biosystems. 2023 Oct 12. pii: S0303-2647(23)00213-7. [Epub ahead of print] 105038

The metabolic control theory: Its development and its application to mitochondrial oxidative phosphorylation.

Jean-Pierre Mazat.

  Metabolic Control Theory (MCT) and Metabolic Control Analysis (MCA) are the two sides, theoretical and experimental, of the measurement of the sensitivity of metabolic networks in the vicinity of a steady state. We will describe the birth and the development of this theory from the first analyses of linear pathways up to a global mathematical theory applicable to any metabolic network. We will describe how the theory, given the global nature of mitochondrial oxidative phosphorylation, solved the problem of what controls mitochondrial ATP synthesis and then how it led to a better understanding of the differential tissue expression of human mitochondrial pathologies and of the heteroplasmy of mitochondrial DNA, leading to the concept of the threshold effect.

Keywords:  Metabolic control analysis; Metabolic control theory; Mitochondrial diseases; Oxidative phoshorylation

DOI:  https://doi.org/10.1016/j.biosystems.2023.105038
Cancer Res. 2023 Oct 17.

Delineating a role for methionine metabolism in colorectal cancer.

Shiyu Liu, Jason W Locasale.

Advances in mass spectrometry allow for broader applications of metabolomics in research and clinical applications. In a recent issue of Nature Metabolism, Voorde and colleagues utilized metabolite profiling to investigate the metabolism of colorectal cancer (CRC) in mouse models, organoids and patients. This study underscores the utility of metabolomics in distinguishing CRC, offering potential for its use in precision medicine. It also revealed a pivotal role for adenosylhomocysteinase in the methionine cycle and highlighted its potential as a therapeutic target.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3169
Curr Opin Biotechnol. 2023 Oct 18. pii: S0958-1669(23)00118-0. [Epub ahead of print]84 103008

Nucleotide metabolism in the regulation of tumor microenvironment and immune cell function.

Helena B Madsen, Marlies Jw Peeters, Per Thor Straten, Claus Desler.

Nucleotide metabolism plays a crucial role in the regulation of the tumor microenvironment (TME) and immune cell function. In the TME, limited availability of nucleotide precursors due to increased consumption by tumor cells and T cells affects both tumor development and immune function. Metabolic reprogramming in tumor cells favors pathways supporting growth and proliferation, including nucleotide synthesis. Additionally, extracellular nucleotides, such as ATP and adenosine, exhibit dual roles in modulating immune function and tumor cell survival. ATP stimulates antitumor immunity by activating purinergic receptors, while adenosine acts as a potent immunosuppressor. Targeting nucleotide metabolism in the TME holds immense promise for cancer therapy. Understanding the intricate relationship between nucleotide metabolism, the TME, and immune responses will pave the way for innovative therapeutic interventions.

DOI: https://doi.org/10.1016/j.copbio.2023.103008
Cancer Drug Resist. 2023 ;6(3): 547-566

A comprehensive overview of recent developments on the mechanisms and pathways of ferroptosis in cancer: the potential implications for therapeutic strategies in ovarian cancer.

Hiroshi Kobayashi, Chiharu Yoshimoto, Sho Matsubara, Hiroshi Shigetomi, Shogo Imanaka.

  Cancer cells adapt to environmental changes and alter their metabolic pathways to promote survival and proliferation. Metabolic reprogramming not only allows tumor cells to maintain a reduction-oxidation balance by rewiring resources for survival, but also causes nutrient addiction or metabolic vulnerability. Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides. Excess iron in ovarian cancer amplifies free oxidative radicals and drives the Fenton reaction, thereby inducing ferroptosis. However, ovarian cancer is characterized by ferroptosis resistance. Therefore, the induction of ferroptosis is an exciting new targeted therapy for ovarian cancer. In this review, potential metabolic pathways targeting ferroptosis were summarized to promote anticancer effects, and current knowledge and future perspectives on ferroptosis for ovarian cancer therapy were discussed. Two therapeutic strategies were highlighted in this review: directly inducing the ferroptosis pathway and targeting metabolic vulnerabilities that affect ferroptosis. The overexpression of SLC7A11, a cystine/glutamate antiporter SLC7A11 (also known as xCT), is involved in the suppression of ferroptosis. xCT inhibition by ferroptosis inducers (e.g., erastin) can promote cell death when carbon as an energy source of glucose, glutamine, or fatty acids is abundant. On the contrary, xCT regulation has been reported to be highly dependent on the metabolic vulnerability. Drugs that target intrinsic metabolic vulnerabilities (e.g., GLUT1 inhibitors, PDK4 inhibitors, or glutaminase inhibitors) predispose cancer cells to death, which is triggered by decreased nicotinamide adenine dinucleotide phosphate generation or increased reactive oxygen species accumulation. Therefore, therapeutic approaches that either directly inhibit the xCT pathway or target metabolic vulnerabilities may be effective in overcoming ferroptosis resistance. Real-time monitoring of changes in metabolic pathways may aid in selecting personalized treatment modalities. Despite the rapid development of ferroptosis-inducing agents, therapeutic strategies targeting metabolic vulnerability remain in their infancy. Thus, further studies must be conducted to comprehensively understand the precise mechanism linking metabolic rewiring with ferroptosis.

Keywords:  Ferroptosis; glutaminolysis; glycolysis; metabolic vulnerability; ovarian cancer; pentose phosphate pathway

DOI:  https://doi.org/10.20517/cdr.2023.49
Biomed Pharmacother. 2023 Oct 16. pii: S0753-3322(23)01511-1. [Epub ahead of print]168 115713

Targeting succinylation-mediated metabolic reprogramming as a potential approach for cancer therapy.

Zhenya Liu, Runxian Wang, Yunshan Wang, Yangmiao Duan, Hanxiang Zhan.

  Metabolic reprogramming is a common hallmark of cancers and involves alterations in many metabolic pathways during tumor initiation and progression. However, the cancer-specific modulation of metabolic reprogramming requires further elucidation. Succinylation, a newly identified protein posttranslational modification (PTM), participates in many cellular processes by transferring a succinyl group to a residue of the target protein, which is related to various pathological disorders including cancers. In recent years, there has been a gradual increase in the number of studies on the regulation of tumors by protein succinylation. Notably, accumulating evidence suggests that succinylation can mediate cancer cell metabolism by altering the structure or activity of metabolism-related proteins and plays vital roles in metabolic reprogramming. Furthermore, some antitumor drugs have been linked to succinylation-mediated tumor-associated metabolism. To better elucidate lysine succinylation mediated tumor metabolic reprogramming, this review mainly summarizes recent studies on the regulation and effects of protein succinylation in tumors, focusing on the metabolic regulation of tumorigenesis and development, which will provide new directions for cancer diagnosis as well as possible therapeutic targets.

Keywords:  Cancer; Metabolic reprogramming; PTM; Succinylation; Treatment

DOI:  https://doi.org/10.1016/j.biopha.2023.115713
Sci Rep. 2023 Oct 18. 13(1): 17733

Warburg-associated acidification represses lactic fermentation independently of lactate, contribution from real-time NMR on cell-free systems.

Zoé Daverio, Maxime Kolkman, Johan Perrier, Lexane Brunet, Nadia Bendridi, Corinne Sanglar, Marie-Agnès Berger, Baptiste Panthu, Gilles J P Rautureau.

Lactate accumulation and acidification in tumours are a cancer hallmark associated with the Warburg effect. Lactic acidosis correlates with cancer malignancy, and the benefit it offers to tumours has been the subject of numerous hypotheses. Strikingly, lactic acidosis enhances cancer cell survival to environmental glucose depletion by repressing high-rate glycolysis and lactic fermentation, and promoting an oxidative metabolism involving reactivated respiration. We used real-time NMR to evaluate how cytosolic lactate accumulation up to 40 mM and acidification up to pH 6.5 individually impact glucose consumption, lactate production and pyruvate evolution in isolated cytosols. We used a reductive cell-free system (CFS) to specifically study cytosolic metabolism independently of other Warburg-regulatory mechanisms found in the cell. We assessed the impact of lactate and acidification on the Warburg metabolism of cancer cytosols, and whether this effect extended to different cytosolic phenotypes of lactic fermentation and cancer. We observed that moderate acidification, independently of lactate concentration, drastically reduces the glucose consumption rate and halts lactate production in different lactic fermentation phenotypes. In parallel, for Warburg-type CFS lactate supplementation induces pyruvate accumulation at control pH, and can maintain a higher cytosolic pyruvate pool at low pH. Altogether, we demonstrate that intracellular acidification accounts for the direct repression of lactic fermentation by the Warburg-associated lactic acidosis.

DOI: https://doi.org/10.1038/s41598-023-44783-3
Oncogene. 2023 Oct 18.

Metabolic control of cancer metastasis: role of amino acids at secondary organ sites.

Breelyn Karno, Deanna N Edwards, Jin Chen.

Most cancer-related deaths are caused by the metastases, which commonly develop at multiple organ sites including the brain, bone, and lungs. Despite longstanding observations that the spread of cancer is not random, our understanding of the mechanisms that underlie metastatic spread to specific organs remains limited. However, metabolism has recently emerged as an important contributor to metastasis. Amino acids are a significant nutrient source to cancer cells and their metabolism which can serve to fuel biosynthetic pathways capable of facilitating cell survival and tumor expansion while also defending against oxidative stress. Compared to the primary tumor, each of the common metastatic sites exhibit vastly different nutrient compositions and environmental stressors, necessitating the need of cancer cells to metabolically thrive in their new environment during colonization and outgrowth. This review seeks to summarize the current literature on amino acid metabolism pathways that support metastasis to common secondary sites, including impacts on immune responses. Understanding the role of amino acids in secondary organ sites may offer opportunities for therapeutic inhibition of cancer metastasis.

DOI: https://doi.org/10.1038/s41388-023-02868-3
Phytomedicine. 2023 Sep 12. pii: S0944-7113(23)00439-7. [Epub ahead of print]122 155079

Timosaponin AIII induces lipid peroxidation and ferroptosis by enhancing Rab7-mediated lipophagy in colorectal cancer cells.

Chenjie Shen, Jinging Liu, Huan Liu, Guifang Li, Hanyu Wang, Haixia Tian, Yong Mao, Dong Hua.

   BACKGROUND: Colorectal cancer (CRC) is a common digestive system malignancy, and despite significant therapeutic advancements, more effective treatments are needed. Timosaponin AIII (TA-III), a major steroidal saponin derived from Anemarrhena asphodeloides Bge, is a potential anticancer agent. Ferroptosis plays an important role in cancer treatment.
PURPOSE: To investigate the molecular mechanism of TA-III as a novel ferroptosis inducer in suppressing CRC through lipophagy. Ferroptosis, an autophagy-dependent mode of cell death, has been implicated in CRC.
METHODS: CRC cells were treated with TA-III, and lipophagy levels were evaluated via BODIPY493/503 staining and western blotting. Autophagy turnover was tracked using GFP-RFP-LC3B. Lipid peroxidation was quantified using an malondialdehyde kit and C11-BODIPY flow assay. Mitochondrial morphology was observed using transmission electron microscopy. GC-MS/MS was used to detect lipid metabolism changes. The role of ras related protein Rab 7a (Rab7) was assessed by western blotting and glutathione S-transferase pull-down assays. In vivo, the anticancer efficacy of TA-III was tested using a xenograft model.
RESULTS: RNA-seq analysis unveiled the potential of TA-III as an anticancer agent through ferroptosis. In vivo experiments revealed how TA-III treatment triggered degradation of lipid droplets in CRC cells, resulting in an accumulation of FFAs, heightened unsaturated free fatty acids, and increased lipid peroxidation. These events ultimately lead to mitochondrial shrinkage and downregulation of ferroptosis markers (FSP1 and GPX4). Intriguingly, the Rab7 protein emerged as a crucial bridge between lipophagy and ferroptosis, underlining its significance in the anticancer mechanism of TA-III. Moreover, TA-III treatment in a xenograft tumour model substantially reduced tumour volume via ferroptosis, underscoring its therapeutic efficacy.
CONLUSION: Our study is the first to establish that TA-III triggers lipophagy in CRC cells via the Rab7 gene, subsequently promoting ferroptosis. This suggests its potential use as an antitumour agent.

Keywords:  Colorectal cancer; Ferroptosis; Lipophagy; Rab7

DOI:  https://doi.org/10.1016/j.phymed.2023.155079
Int Immunol. 2023 Oct 14. pii: dxad035. [Epub ahead of print]

Metabolic advantages of regulatory T cells dictated by cancer cells.

Masaki Kondo, Shogo Kumagai, Hiroyoshi Nishikawa.

  Cancer cells employ glycolysis for their survival and growth (the 'Warburg effect'). Consequently, surrounding cells including immune cells in the tumor microenvironment (TME) are exposed to hypoglycemic, hypoxic, and low pH circumstances. Since effector T cells depend on the glycolysis for their survival and functions, the metabolically harsh TME established by cancer cells is unfavorable, resulting in the impairment of effective antitumor immune responses. By contrast, immunosuppressive cells such as regulatory T (Treg) cells can infiltrate, proliferate, survive, and exert immunosuppressive functions in the metabolically harsh TME, indicating the different metabolic dependance between effector T cells and Treg cells. Indeed, some metabolites that are harmful for effector T cells can be utilized by Treg cells; lactic acid, a harmful metabolite for effector T cells, is available for Treg cell proliferation and functions. Deficiency of amino acids such as tryptophan and glutamine in the TME impairs effector T cell activation but increases Treg cell populations. Furthermore, hypoxia upregulates fatty acid oxidation via hypoxia-inducible factor 1α (HIF-1α) and promotes Treg cell migration. Adenosine is induced by the ectonucleotidases CD39 and CD73, which are strongly induced by HIF-1α, and reportedly accelerates Treg cell development by upregulating Foxp3 expression in T cells via A2AR-mediated signals. Therefore, this review focuses on the current views of the unique metabolism of Treg cells dictated by cancer cells. In addition, potential cancer combination therapies with immunotherapy and metabolic molecularly targeted reagents that modulate Treg cells in the TME are discussed to develop 'immune metabolism-based precision medicine'.

Keywords:  metabolism; regulatory T cell

DOI:  https://doi.org/10.1093/intimm/dxad035
J Nutr. 2023 Oct 17. pii: S0022-3166(23)72665-5. [Epub ahead of print]

Dietary galactose increases the expression of mitochondrial OXPHOS genes and modulates the carbohydrate oxidation pathways in mouse intestinal mucosa.

Ferran S Fos-Codoner, Lianne M S Bouwman, Jaap Keijer, Evert M van Schothorst.

   BACKGROUND: Prolonged lactation provides substantial health benefits, potentially due to galactose as part of milk sugar lactose. Isocaloric replacing dietary glucose (16energy%) by galactose within a normal diet (64en% carbohydrates) during a 3 week post-weaning period provided substantial benefits on short- and long-term physiological and metabolic parameters at whole body level and liver in female mice, which might be attributable to intestinal function.
OBJECTIVE: The aim of this study was to investigate if partial dietary replacement of glucose by galactose alters intestinal metabolism underlying hepatic health effects.
METHODS: Proximal intestinal mucosa gene profiles in female mice using RNAseq technology were analyzed, validated, and correlated to hepatic health parameters.
RESULTS: Transcriptome analysis revealed that the presence of galactose primarily affected pathways involved in energy metabolism. In the subset of mitochondrial transcripts, a consistent higher expression was observed (78 of 80, all P.adjusted<0.1). Oxidative phosphorylation represented the most upregulated process (all top 10 pathways), independent of total mitochondrial mass (P=0.75). Moreover, galactose consistently upregulated carbohydrate metabolism pathways, specifically glycolysis till acetyl-CoA production, and fructose metabolism. Also, the expression of transcripts involved in these pathways negatively correlated with circulating serum amyloid A3 protein, a marker of hepatic inflammation (R[-0.61, -0.5], P[0.002, 0.01]). In agreement, CD163+ cells were decreased in the liver. Additionally, the expression of key fructolytic enzymes in the small intestinal mucosa negatively correlated with triglycerides accumulation in the liver (R[-0.45, -0.4], P[0.03, 0.05]).
CONCLUSIONS: Our results show for the first time in vivo the role of galactose as an oxidative phosphorylation activator. Moreover, the concept of intestinal cells acting as the body's metabolic gatekeeper is strongly supported, as they alter substrate availability and thereby contribute to the maintenance of metabolic homeostasis, protecting other organs, as evidenced by their potential ability to shield the liver from potential detrimental effects of fructose.

Keywords:  Mouse; OXPHOS; RNA-seq; carbohydrate metabolism; galactose; gut-liver axis; lactose; mitochondria

DOI:  https://doi.org/10.1016/j.tjnut.2023.10.011
Cell Metab. 2023 Oct 10. pii: S1550-4131(23)00368-6. [Epub ahead of print]

CD36 maintains lipid homeostasis via selective uptake of monounsaturated fatty acids during matrix detachment and tumor progression.

Alexander R Terry, Veronique Nogueira, Hyunsoo Rho, Gopalakrishnan Ramakrishnan, Jing Li, Soeun Kang, Koralege C Pathmasiri, Sameer Ahmed Bhat, Liping Jiang, Shafi Kuchay, Stephanie M Cologna, Nissim Hay.

  A high-fat diet (HFD) promotes metastasis through increased uptake of saturated fatty acids (SFAs). The fatty acid transporter CD36 has been implicated in this process, but a detailed understanding of CD36 function is lacking. During matrix detachment, endoplasmic reticulum (ER) stress reduces SCD1 protein, resulting in increased lipid saturation. Subsequently, CD36 is induced in a p38- and AMPK-dependent manner to promote preferential uptake of monounsaturated fatty acids (MUFAs), thereby maintaining a balance between SFAs and MUFAs. In attached cells, CD36 palmitoylation is required for MUFA uptake and protection from palmitate-induced lipotoxicity. In breast cancer mouse models, CD36-deficiency induced ER stress while diminishing the pro-metastatic effect of HFD, and only a palmitoylation-proficient CD36 rescued this effect. Finally, AMPK-deficient tumors have reduced CD36 expression and are metastatically impaired, but ectopic CD36 expression restores their metastatic potential. Our results suggest that, rather than facilitating HFD-driven tumorigenesis, CD36 plays a supportive role by preventing SFA-induced lipotoxicity.

Keywords:  CD36; cancer metabolism; fatty acids; matrix detachment; metastasis; palmitoylation

DOI:  https://doi.org/10.1016/j.cmet.2023.09.012
Genome Biol. 2023 Oct 17. 24(1): 234

Single-cell metabolic profiling reveals subgroups of primary human hepatocytes with heterogeneous responses to drug challenge.

Eva Sanchez-Quant, Maria Lucia Richter, Maria Colomé-Tatché, Celia Pilar Martinez-Jimenez.

   BACKGROUND: Xenobiotics are primarily metabolized by hepatocytes in the liver, and primary human hepatocytes are the gold standard model for the assessment of drug efficacy, safety, and toxicity in the early phases of drug development. Recent advances in single-cell genomics demonstrate liver zonation and ploidy as main drivers of cellular heterogeneity. However, little is known about the impact of hepatocyte specialization on liver function upon metabolic challenge, including hepatic metabolism, detoxification, and protein synthesis.
RESULTS: Here, we investigate the metabolic capacity of individual human hepatocytes in vitro. We assess how chronic accumulation of lipids enhances cellular heterogeneity and impairs the metabolisms of drugs. Using a phenotyping five-probe cocktail, we identify four functional subgroups of hepatocytes responding differently to drug challenge and fatty acid accumulation. These four subgroups display differential gene expression profiles upon cocktail treatment and xenobiotic metabolism-related specialization. Notably, intracellular fat accumulation leads to increased transcriptional variability and diminishes the drug-related metabolic capacity of hepatocytes.
CONCLUSIONS: Our results demonstrate that, upon a metabolic challenge such as exposure to drugs or intracellular fat accumulation, hepatocyte subgroups display different and heterogeneous transcriptional responses.

Keywords:  Cytochrome P450; DILI; Drug metabolism; Hepatic steatosis; Lipid metabolism; Liver; NAFLD; Primary human hepatocytes; Single-cell transcriptomics

DOI:  https://doi.org/10.1186/s13059-023-03075-9
Front Pharmacol. 2023 ;14 1264032

Phenethyl isothiocyanate and dasatinib combination synergistically reduces hepatocellular carcinoma growth via cell cycle arrest and oxeiptosis.

Gabriele Strusi, Caterina M Suelzu, Nicole Horwood, Andrea E Münsterberg, Yongping Bao.

  Introduction: Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which is among the most lethal tumours. Combination therapy exploits multiple drugs to target key pathways synergistically to reduce tumour growth. Isothiocyanates have been shown to possess anticancer potential and to complement the anticancer activity of other compounds. This study aimed to investigate the potential of phenethyl isothiocyanate (PEITC) to synergise with dasatinib, improving its anticancer potential in HCC. Methods: MTT, 3D spheroids and clonogenic assays were used to assess the combination anti-tumour effect in vitro, whereas a murine syngeneic model was employed to evaluate the combination efficacy in vivo. DCFDA staining was employed to evaluate the production of reactive oxygen species (ROS), while flow cytometry and Western blot assays were used to elucidate the molecular mechanism of the synergistic activiy. Results: PEITC and dasatinib combination exhibited a synergistic effect in vitro and in vivo. The combination induced DNA damage and oxidative stress through the production of ROS, which led to the formation of a premature CDK1/Cyclin B1 complex associated with induction of mitotic catastrophe. Furthermore, ROS activated oxeiptosis, a caspase-independent form of programmed cell death. Conclusion: PEITC showed to enhance dasatinib action in treating HCC with increased production of ROS that induced cell cycle arrest followed by mitotic catastrophe, and to induce oxeiptosis. These results highlight the role that ITCs may have in cancer therapy as a complement of clinically approved chemotherapeutic drugs.

Keywords:  PEITC; cancer therapeutics; combination therapy; dasatinib; drug development; oncology; oxeiptosis

DOI:  https://doi.org/10.3389/fphar.2023.1264032
Neurobiol Dis. 2023 Oct 13. pii: S0969-9961(23)00343-1. [Epub ahead of print] 106327

Metabolic remodeling in astrocytes: Paving the path to brain tumor development.

Myriam Jaraíz-Rodríguez, Lucia Del Prado, Eduardo Balsa.

  The brain is a highly metabolic organ, composed of multiple cell classes, that controls crucial functions of the body. Although neurons have traditionally been the main protagonist, astrocytes have gained significant attention over the last decade. In this regard, astrocytes are a type of glial cells that have recently emerged as critical regulators of central nervous system (CNS) function and play a significant role in maintaining brain energy metabolism. However, in certain scenarios, astrocyte behavior can go awry, which poses a significant threat to brain integrity and function. This is definitively the case for mutations that turn normal astrocytes and astrocytic precursors into gliomas, an aggressive type of brain tumor. In addition, healthy astrocytes can interact with tumor cells, becoming part of the tumor microenvironment and influencing disease progression. In this review, we discuss the recent evidence suggesting that disturbed metabolism in astrocytes can contribute to the development and progression of fatal human diseases such as cancer. Emphasis is placed on detailing the molecular bases and metabolic pathways of this disease and highlighting unique metabolic vulnerabilities that can potentially be exploited to develop successful therapeutic opportunities.

Keywords:  Astrocytes; Astrocytoma; Cancer; Glioma; Metabolism

DOI:  https://doi.org/10.1016/j.nbd.2023.106327
ACS Biomater Sci Eng. 2023 Oct 19.

Preparation of a Mesoporous Biosensor for Human Lactate Dehydrogenase for Potential Anticancer Inhibitor Screening.

Clarissa Cocuzza, Elena Antoniono, Carminna Ottone, Valentina Cauda, Debora Fino, Marco Piumetti.

  Cancer is the second leading cause of death worldwide, with a dramatic impact due to the acquired resistance of cancers to used chemotherapeutic drugs and treatments. The enzyme lactate dehydrogenase (LDH-A) is responsible for cancer cell proliferation. Recently the development of selective LDH-A inhibitors as drugs for cancer treatment has been reported to be an efficient strategy aiming to decrease cancer cell proliferation and increase the sensitivity to traditional chemotherapeutics. This study aims to obtain a stable and active biocatalyst that can be utilized for such drug screening purposes. It is conceived by adopting human LDH-A enzyme (hLDH-A) and investigating different immobilization techniques on porous supports to achieve a stable and reproducible biosensor for anticancer drugs. The hLDH-A enzyme is covalently immobilized on mesoporous silica (MCM-41) functionalized with amino and aldehyde groups following two different methods. The mesoporous support is characterized by complementary techniques to evaluate the surface chemistry and the porous structure. Fluorescence microscopy analysis confirms the presence of the enzyme on the support surface. The tested immobilizations achieve yields of ≥80%, and the best retained activity of the enzyme is as high as 24.2%. The optimal pH and temperature of the best immobilized hLDH-A are pH 5 and 45 °C for the reduction of pyruvate into lactate, while those for the free enzyme are pH 8 and 45 °C. The stability test carried out at 45 °C on the immobilized enzyme shows a residual activity close to 40% for an extended time. The inhibition caused by NHI-2 is similar for free and immobilized hLDH-A, 48% and 47%, respectively. These findings are significant for those interested in immobilizing enzymes through covalent attachment on inorganic porous supports and pave the way to develop stable and active biocatalyst-based sensors for drug screenings that are useful to propose drug-based cancer treatments.

Keywords:  MCM-41; NHI-2; covalent attachment; enzyme immobilization; hLDH-A; human lactate dehydrogenase; mesoporous silica

DOI:  https://doi.org/10.1021/acsbiomaterials.3c00582
Biochem Pharmacol. 2023 Oct 13. pii: S0006-2952(23)00447-1. [Epub ahead of print]217 115856

M4IDP stimulates ROS elevation through inhibition of mevalonate pathway and pentose phosphate pathway to inhibit colon cancer cells.

Ying Peng, Qing-Zhu Liu, Dong Xu, Jia-Yu Fu, Li-Xia Zhang, Ling Qiu, Jian-Guo Lin.

  Maintaining redox homeostasis is an essential feature of cancer cells, and disrupting this homeostasis to cause oxidative stress and induce cell death is an important strategy in cancer therapy. M4IDP, a zoledronic acid derivative, can cause the death of human colorectal cancer cells by increasing the level of intracellular reactive oxygen species (ROS). However, its potential molecular mechanism is unclear. Our in vitro studies showed that treatment with M4IDP promoted oxidative stress in HCT116 cells, as measured by the decreased ratios of GSH/GSSG and NADPH/NADP+ and increased level of MDA. M4IDP could cause the decrease of GSH content, the increase of GSSG content, the decrease of NADPH content and pentose phosphate pathway flux, the downregulation of G6PD expression, the upregulation of unprenylated Rap1A and total expression of RhoA and CDC42. The increase of ROS and cytotoxicity induced by M4IDP could be reversed by the supplementation of NADPH, the overexpression of G6PD and the supplementation of GGOH. In vivo studies showed that M4IDP inhibited tumor growth in the human colorectal cancer xenograft mouse model, which was accompanied with a decreased [18F]FDG uptake. Collectively, these results provide evidence that M4IDP can promote oxidation in colon cancer cells by inhibiting mevalonate pathway and pentose phosphate pathway and produce therapeutic effect. This study revealed for the first time a possible mechanism of bisphosphonate-induced increase of ROS in malignant tumor cells. This is helpful for the development of new molecular therapeutic targets and can provide new ideas for the combined therapy of bisphosphonates in tumors.

Keywords:  Bisphosphonate; Colorectal cancer; Mevalonate pathway; Pentose phosphate pathway; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.bcp.2023.115856
Cancer Discov. 2023 Oct 18.

Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer.

Sarah P Suehnholz, Moriah H Nissan, Hongxin Zhang, Ritika Kundra, Subhiksha Nandakumar, Calvin Lu, Stephanie Carrero, Amanda Dhaneshwar, Nicole Fernandez, Benjamin W Xu, Maria E Arcila, Ahmet Zehir, Aijazuddin Syed, A Rose Brannon, Julia E Rudolph, Eder Paraiso, Paul J Sabbatini, Ross L Levine, Ahmet Dogan, Jianjiong Gao, Marc Ladanyi, Alexander Drilon, Michael F Berger, David B Solit, Nikolaus Schultz, Debyani Chakravarty.

There is a continuing debate about the proportion of cancer patients that benefit from precision oncology, attributable in part to conflicting views as to which molecular alterations are clinically actionable. To quantify the expansion of clinical actionability since 2017, we annotated 47,271 solid tumors sequenced with the MSK-IMPACT clinical assay using two temporally distinct versions of the OncoKB knowledge base deployed 5 years apart. Between 2017 and 2022, we observed an increase from 8.9% to 31.6% in the fraction of tumors harboring a standard care (Level 1 or 2) predictive biomarker of therapy response and an almost halving of tumors carrying non-actionable drivers (44.2% to 22.8%). In tumors with limited or no clinical actionability, TP53 (43.2%), KRAS (19.2%) and CDKN2A (12.2%) were the most frequently altered genes.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0467
Cancer Cytopathol. 2023 Oct 16.

Unlocking the potential of organoids in cancer treatment and translational research: An application of cytologic techniques.

Mohamed A Abd El-Salam, Maria J Troulis, Chong-Xian Pan, Rema A Rao.

  Patient-derived organoid models hold promise for advancing clinical cancer research, including diagnosis and personalized and precision medicine approaches, and cytology, in particular, plays a pivotal role in this process. These three-dimensional multicellular structures are heterogeneous, potentially maintain the cancer phenotype, and conserve the genomic, transcriptomic, and epigenomic patterns of the parental tumors. To ensure that only tumor tissue is used for organoid development, cytologic validation is necessary before initiating the process of organoid generation. Here, we explore the technology of tumor organoids and discuss the fundamental application of cytology as a simple and cost-effective approach toward organoid development. We also underscore the potential application of organoid development in drug efficacy studies for lung cancer and head and neck tumors. Additionally, we stress the importance of using fine-needle aspiration to generate tumoroids.

Keywords:  cytology smears; head and neck cancer; lung cancer; organoids; personalized and precision medicine; rare tumors; tumoroids

DOI:  https://doi.org/10.1002/cncy.22769
Neurochem Int. 2023 Oct 12. pii: S0197-0186(23)00154-7. [Epub ahead of print]171 105626

Stable isotope tracing reveals disturbed cellular energy and glutamate metabolism in hippocampal slices of aged male mice.

Laura Mikél McNair, Jens Velde Andersen, Helle Sønderby Waagepetersen.

  Neurons and astrocytes work in close metabolic collaboration, linking neurotransmission to brain energy and neurotransmitter metabolism. Dysregulated energy metabolism is a hallmark of the aging brain and may underlie the progressive age-dependent cognitive decline. However, astrocyte and neurotransmitter metabolism remains understudied in aging brain research. In particular, how aging affects metabolism of glutamate, being the primary excitatory neurotransmitter, is still poorly understood. Here we investigated critical aspects of cellular energy metabolism in the aging male mouse hippocampus using stable isotope tracing in vitro. Metabolism of [U-13C]glucose demonstrated an elevated glycolytic capacity of aged hippocampal slices, whereas oxidative [U-13C]glucose metabolism in the TCA cycle was significantly reduced with aging. In addition, metabolism of [1,2-13C]acetate, reflecting astrocyte energy metabolism, was likewise reduced in the hippocampal slices of old mice. In contrast, uptake and subsequent metabolism of [U-13C]glutamate was elevated, suggesting increased capacity for cellular glutamate handling with aging. Finally, metabolism of [15N]glutamate was maintained in the aged slices, demonstrating sustained glutamate nitrogen metabolism. Collectively, this study reveals fundamental alterations in cellular energy and neurotransmitter metabolism in the aging brain, which may contribute to age-related hippocampal deficits.

Keywords:  Astrocytes; Glutamate uptake; Glutamate-glutamine cycle; Isotope tracing

DOI:  https://doi.org/10.1016/j.neuint.2023.105626
Adv Exp Med Biol. 2023 ;1438 121-126

The Impact of Heterogeneous Cell Density in Hypoxic Tumors Treated with Radiotherapy.

Filippo Schiavo, Iuliana Toma-Dasu, Emely Kjellsson Lindblom.

  Hypoxia is frequently found in solid tumors and is known to increase the resistance to several kinds of treatment modalities including radiation therapy. Besides, the treatment response is also largely determined by the total number of clonogenic cells, i.e., cells with unlimited proliferative capacity. Depending on the duration of hypoxia, the rate of proliferation and hence also the clonogen density could be expected to differ in hypoxic compartments. The combination at the microscale between heterogeneous tumor oxygenation and clonogen density could therefore be crucial with respect to the outcome of a radiotherapy treatment. In this study it was investigated the impact of heterogeneous clonogen density on the outcome of stereotactic radiotherapy treatments of hypoxic tumors. A recently developed three-dimensional model for tissue vasculature and oxygenation was used to create realistic in silico tumors with heterogeneous oxygenation. Stereotactic radiotherapy treatments were simulated, and cell survival was calculated on a voxel-level accounting for the oxygenation. For a tumor with a diameter of 1 cm and a baseline clonogenic density of 107/cm3 for the normoxic subvolume, when the relative density for the hypoxic cells drops by a factor of 10 the tumor control probability (TCP) decreases by about 10% when relatively small hypoxic volumes and few fractions are considered; longer treatments tend to level out the results. With increasing size of the hypoxic subvolume, the TCP decreased overall as expected, and the difference in TCP between a homogeneous and a heterogeneous distribution of cells increased. The results demonstrate a delicate interplay between the heterogeneous distribution of tumor oxygenation and clonogenic cells that could significantly impact on the treatment outcome of radiotherapy.

Keywords:  Hypoxia; Radiotherapy; Tumors

DOI:  https://doi.org/10.1007/978-3-031-42003-0_20