bims-medica 2023-11-26 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2023‒11‒26
28 papers selected by
Brett Chrest, East Carolina University

Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance.
Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia.
Proline and dihydroorotate dehydrogenase promote a hyper-proliferative state and dampen ferroptosis in cancer cells by rewiring mitochondrial redox metabolism.
Therapeutic Dosage of Antipsychotic Drug Aripiprazole Induces Persistent Mitochondrial Hyperpolarisation, Moderate Oxidative Stress in Liver Cells, and Haemolysis.
KATP channel activity and slow oscillations in pancreatic beta cells are regulated by mitochondrial ATP production.
Senescent Endothelial Cells Sustain Their Senescence-Associated Secretory Phenotype (SASP) through Enhanced Fatty Acid Oxidation.
Adaptive changes in tumor cells in response to reductive stress.
Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution.
Mitochondrial hyperfusion induces metabolic remodeling in lung endothelial cells by modifying the activities of electron transport chain complexes I and III.
Vitamin B5 Supports Oncogenic Metabolism in MYC-Driven Breast Cancer.
Multiomics of HER2-low triple-negative breast cancer identifies a receptor tyrosine kinase-relevant subgroup with therapeutic prospects.
Ferroptosis resistance in cancer: recent advances and future perspectives.
High Fat Diet-Induced Obesity Dysregulates Splenic B Cell Mitochondrial Activity.
Treatment of Acute Myeloid Leukemia in Older Adults.
Oxidative stress accompanies HIF1-dependent impairment of glucose metabolism in the hippocampus of adult rats survived prenatal severe hypoxia.
Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML.
The effect of lactate dehydrogenase inhibitors on proliferation, motility and invasion of breast cancer cells in vitro highlights a new role for lactate.
Aerobic glycolysis is the predominant means of glucose metabolism in neuronal somata, which protects against oxidative damage.
Exploiting iron metabolism as a therapeutic vulnerability in glioblastoma.
Reducing Dietary Polyunsaturated to Saturated Fatty Acids Ratio Improves Lipid and Glucose Metabolism in Obese Zucker Rats.
Pediatric acute myeloid leukemia - novel approaches.
Cell-specific modulation of mitochondrial respiration and metabolism by the pro-apoptotic Bcl-2 family members Bax and Bak.
Is ketogenic diet a 'precision medicine'? Recent developments and future challenges.
Methods for Oxygen Determination in an NMR Bioreactor as a Surrogate Marker for Metabolomic Studies in Living Cell Cultures.
Preclinical characterization of danatinib as a novel FLT3 inhibitor with excellent efficacy against resistant acute myeloid leukemia.
A distinct Acyl-CoA binding protein (ACBP6) shapes tissue plasticity during nutrient adaptation in Drosophila.
Targeting ferroptosis in melanoma: cancer therapeutics.
Serine synthesis pathway enzyme PHGDH is critical for muscle cell biomass, anabolic metabolism and mTORC1 signaling.

Pharmaceutics. 2023 Nov 10. pii: 2610. [Epub ahead of print]15(11):

Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance.

Andrea Cunha, Patrícia M A Silva, Bruno Sarmento, Odília Queirós.

  The "Warburg effect" consists of a metabolic shift in energy production from oxidative phosphorylation to glycolysis. The continuous activation of glycolysis in cancer cells causes rapid energy production and an increase in lactate, leading to the acidification of the tumour microenvironment, chemo- and radioresistance, as well as poor patient survival. Nevertheless, the mitochondrial metabolism can be also involved in aggressive cancer characteristics. The metabolic differences between cancer and normal tissues can be considered the Achilles heel of cancer, offering a strategy for new therapies. One of the main causes of treatment resistance consists of the increased expression of efflux pumps, and multidrug resistance (MDR) proteins, which are able to export chemotherapeutics out of the cell. Cells expressing MDR proteins require ATP to mediate the efflux of their drug substrates. Thus, inhibition of the main energy-producing pathways in cancer cells, not only induces cancer cell death per se, but also overcomes multidrug resistance. Given that most anticancer drugs do not have the ability to distinguish normal cells from cancer cells, a number of drug delivery systems have been developed. These nanodrug delivery systems provide flexible and effective methods to overcome MDR by facilitating cellular uptake, increasing drug accumulation, reducing drug efflux, improving targeted drug delivery, co-administering synergistic agents, and increasing the half-life of drugs in circulation.

Keywords:  Warburg effect; glycolysis; nanoparticles; resistance; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/pharmaceutics15112610
bioRxiv. 2023 Nov 08. pii: 2023.11.06.565895. [Epub ahead of print]

Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia.

Megan D Radyk, Barbara S Nelson, Christopher J Halbrook, Alexander Wood, Brooke Lavoie, Lucie Salvatore, Gabriel Corfas, Justin A Colacino, Yatrik M Shah, Howard C Crawford, Costas A Lyssiotis.

Activating mutations in KRAS extensively reprogram cellular metabolism to support the continuous growth, proliferation, and survival of pancreatic tumors. Targeting these metabolic dependencies are promising approaches for the treatment of established tumors. However, metabolic reprogramming is required early during tumorigenesis to provide transformed cells selective advantage towards malignancy. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM). Dysregulation of pathways that maintain acinar homeostasis accelerate tumorigenesis. During ADM, acinar cells transdifferentiate to duct-like cells, a process driven by oncogenic KRAS . The metabolic reprogramming that is required for the transdifferentiation in ADM is unclear. We performed transcriptomic analysis on mouse acinar cells undergoing ADM and found metabolic programs are globally enhanced, consistent with the transition of a specialized cell to a less differentiated phenotype with proliferative potential. Indeed, we and others have demonstrated how inhibiting metabolic pathways necessary for ADM can prevent transdifferentiation and tumorigenesis. Here, we also find NRF2-target genes are differentially expressed during ADM. Among these, we focused on the increase in the gene coding for NADPH-producing enzyme, Glucose-6-phosphate dehydrogenase (G6PD). Using established mouse models of Kras G12D -driven pancreatic tumorigenesis and G6PD-deficiency, we find that mutant G6pd accelerates ADM and pancreatic intraepithelial neoplasia. Acceleration of cancer initiation with G6PD-deficiency is dependent on its NADPH-generating function in reactive oxygen species (ROS) management, as opposed to other outputs of the pentose phosphate pathway. Together, this work provides new insights into the function of metabolic pathways during early tumorigenesis.

DOI: https://doi.org/10.1101/2023.11.06.565895
Biochim Biophys Acta Mol Cell Res. 2023 Nov 21. pii: S0167-4889(23)00212-4. [Epub ahead of print] 119639

Proline and dihydroorotate dehydrogenase promote a hyper-proliferative state and dampen ferroptosis in cancer cells by rewiring mitochondrial redox metabolism.

Ryan J Mailloux.

  Redox realignment is integral to the initiation, progression, and metastasis of cancer. This requires considerable metabolic rewiring to induce aberrant shifts in redox homeostasis that favor high hydrogen peroxide (H2O2) generation for the induction of a hyper-proliferative state. The ability of tumor cells to thrive under the oxidative burden imposed by this high H2O2 is achieved by increasing antioxidant defenses. This shift in the redox stress signaling threshold (RST) also dampens ferroptosis, an iron (Fe)-dependent form of cell death activated by oxidative distress and lipid peroxidation reactions. Mitochondria are central to the malignant transformation of normal cells to cancerous ones since these organelles supply building blocks for anabolism, govern ferroptosis, and serve as the major source of cell H2O2. This review summarizes advances in understanding the rewiring of redox reactions in mitochondria to promote carcinogenesis, focusing on how cancer cells hijack the electron transport chain (ETC) to promote proliferation and evasion of ferroptosis. I then apply emerging concepts in redox homeodynamics to discuss how the rewiring of the Krebs cycle and ETC promotes shifts in the RST to favor high rates of H2O2 generation for cell signaling. This discussion then focuses on proline dehydrogenase (PRODH) and dihydroorotate dehydrogenase (DHODH), two enzymes over expressed in cancers, and how their link to one another through the coenzyme Q10 (CoQ) pool generates a redox connection that forms a H2O2 signaling platform and pyrimidine synthesome that favors a hyper-proliferative state and disables ferroptosis.

Keywords:  Dihydroorotate dehydrogenase;; Ferroptosis; Hydrogen peroxide; Proline dehydrogense; Redox stress signaling threshold

DOI:  https://doi.org/10.1016/j.bbamcr.2023.119639
Antioxidants (Basel). 2023 Oct 30. pii: 1930. [Epub ahead of print]12(11):

Therapeutic Dosage of Antipsychotic Drug Aripiprazole Induces Persistent Mitochondrial Hyperpolarisation, Moderate Oxidative Stress in Liver Cells, and Haemolysis.

Tinkara Pirc Marolt, Barbara Kramar, Andrej Vovk, Helena Podgornik, Dušan Šuput, Irina Milisav.

  Aripiprazole has fewer metabolic side effects than other antipsychotics; however, there are some severe ones in the liver, leading to drug-induced liver injury. Repeated treatment with aripiprazole affects cell division. Since this process requires a lot of energy, we decided to investigate the impact of aripiprazole on rat liver cells and mitochondria as the main source of cellular energy production by measuring the mitochondrial membrane potential, respiration, adenosine triphosphate (ATP) production, oxidative stress, antioxidative response, and human blood haemolysis. Here, we report that mitochondrial hyperpolarisation from aripiprazole treatment is accompanied by higher reactive oxygen species (ROS) production and increased antioxidative response. Lower mitochondrial and increased glycolytic ATP synthesis demand more glucose through glycolysis for equal ATP production and may change the partition between the glycolysis and pentose phosphate pathway in the liver. The uniform low amounts of the haemolysis of erythrocytes in the presence of aripiprazole in 25 individuals indicate lower quantities of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH+H+), which is in accordance with a decreased activity of glucose 6-phosphate dehydrogenase and the lower dehydrogenase activity upon aripiprazole treatment. The lower activity of glucose 6-phosphate dehydrogenase supports a shift to glycolysis, thus rescuing the decreased mitochondrial ATP synthesis. The putative reduction in NADPH+H+ did not seem to affect the oxidised-to-reduced glutathione ratio, as it remained equal to that in the untreated cells. The effect of aripiprazole on glutathione reduction is likely through direct binding, thus reducing its total amount. As a consequence, the low haemolysis of human erythrocytes was observed. Aripiprazole causes moderate perturbations in metabolism, possibly with one defect rescuing the other. The result of the increased antioxidant enzyme activity upon treatment with aripiprazole is increased resilience to oxidative stress, which makes it an effective drug for schizophrenia in which oxidative stress is constantly present because of disease and treatment.

Keywords:  aripiprazole; cell respiration; drug-induced liver injury; hepatocytes; hyperpolarisation; mitochondria; olanzapine; schizophrenia

DOI:  https://doi.org/10.3390/antiox12111930
J Physiol. 2023 Nov 20.

KATP channel activity and slow oscillations in pancreatic beta cells are regulated by mitochondrial ATP production.

Jeremías Corradi, Benjamin Thompson, Patrick A Fletcher, Richard Bertram, Arthur S Sherman, Leslie S Satin.

  Pancreatic beta cells secrete insulin in response to plasma glucose. The ATP-sensitive potassium channel (KATP ) links glucose metabolism to islet electrical activity in these cells by responding to increased cytosolic [ATP]/[ADP]. It was recently proposed that pyruvate kinase (PK) in close proximity to beta cell KATP locally produces the ATP that inhibits KATP activity. This proposal was largely based on the observation that applying phosphoenolpyruvate (PEP) and ADP to the cytoplasmic side of excised inside-out patches inhibited KATP . To test the relative contributions of local vs. mitochondrial ATP production, we recorded KATP activity using mouse beta cells and INS-1 832/13 cells. In contrast to prior reports, we could not replicate inhibition of KATP activity by PEP + ADP. However, when the pH of the PEP solutions was not corrected for the addition of PEP, strong channel inhibition was observed as a result of the well-known action of protons to inhibit KATP . In cell-attached recordings, perifusing either a PK activator or an inhibitor had little or no effect on KATP channel closure by glucose, further suggesting that PK is not an important regulator of KATP . In contrast, addition of mitochondrial inhibitors robustly increased KATP activity. Finally, by measuring the [ATP]/[ADP] responses to imposed calcium oscillations in mouse beta cells, we found that oxidative phosphorylation could raise [ATP]/[ADP] even when ADP was at its nadir during the burst silent phase, in agreement with our mathematical model. These results indicate that ATP produced by mitochondrial oxidative phosphorylation is the primary controller of KATP in pancreatic beta cells. KEY POINTS: Phosphoenolpyruvate (PEP) plus adenosine diphosphate does not inhibit KATP activity in excised patches. PEP solutions only inhibit KATP activity if the pH is unbalanced. Modulating pyruvate kinase has minimal effects on KATP activity. Mitochondrial inhibition, in contrast, robustly potentiates KATP activity in cell-attached patches. Although the ADP level falls during the silent phase of calcium oscillations, mitochondria can still produce enough ATP via oxidative phosphorylation to close KATP . Mitochondrial oxidative phosphorylation is therefore the main source of the ATP that inhibits the KATP activity of pancreatic beta cells.

Keywords:  KATP channels; [ATP]/[ADP] ratio; beta cells; glucose response; insulin secretion; oxidative phosphorylation; pH modulation; pyruvate kinase

DOI:  https://doi.org/10.1113/JP284982
Antioxidants (Basel). 2023 Nov 02. pii: 1956. [Epub ahead of print]12(11):

Senescent Endothelial Cells Sustain Their Senescence-Associated Secretory Phenotype (SASP) through Enhanced Fatty Acid Oxidation.

Angelica Giuliani, Anna Maria Giudetti, Daniele Vergara, Laura Del Coco, Deborah Ramini, Sara Caccese, Matilde Sbriscia, Laura Graciotti, Gianluca Fulgenzi, Luca Tiano, Francesco Paolo Fanizzi, Fabiola Olivieri, Maria Rita Rippo, Jacopo Sabbatinelli.

  Cellular senescence is closely linked to endothelial dysfunction, a key factor in age-related vascular diseases. Senescent endothelial cells exhibit a proinflammatory phenotype known as SASP, leading to chronic inflammation (inflammaging) and vascular impairments. Albeit in a state of permanent growth arrest, senescent cells paradoxically display a high metabolic activity. The relationship between metabolism and inflammation is complex and varies across cell types and senescence inductions. While some cell types shift towards glycolysis during senescence, others favor oxidative phosphorylation (OXPHOS). Despite the high availability of oxygen, quiescent endothelial cells (ECs) tend to rely on glycolysis for their bioenergetic needs. However, there are limited data on the metabolic behavior of senescent ECs. Here, we characterized the metabolic profiles of young and senescent human umbilical vein endothelial cells (HUVECs) to establish a possible link between the metabolic status and the proinflammatory phenotype of senescent ECs. Senescent ECs internalize a smaller amount of glucose, have a lower glycolytic rate, and produce/release less lactate than younger cells. On the other hand, an increased fatty acid oxidation activity was observed in senescent HUVECs, together with a greater intracellular content of ATP. Interestingly, blockade of glycolysis with 2-deoxy-D-glucose in young cells resulted in enhanced production of proinflammatory cytokines, while the inhibition of carnitine palmitoyltransferase 1 (CPT1), a key rate-limiting enzyme of fatty acid oxidation, ameliorated the SASP in senescent ECs. In summary, metabolic changes in senescent ECs are complex, and this research seeks to uncover potential strategies for modulating these metabolic pathways to influence the SASP.

Keywords:  endothelial cells; fatty acid oxidation; glycolysis; senescence; senescence-associated secretory phenotype

DOI:  https://doi.org/10.3390/antiox12111956
Biochem Pharmacol. 2023 Nov 22. pii: S0006-2952(23)00522-1. [Epub ahead of print] 115929

Adaptive changes in tumor cells in response to reductive stress.

Leilei Zhang, Jie Zhang, Zhi-Wei Ye, Aslam Muhammad, Li Li, John W Culpepper, Danyelle M Townsend, Kenneth D Tew.

  Reductive stress is characterized by an excess of cellular electron donors and can be linked with various human pathologies including cancer. We developed melanoma cell lines resistant to reductive stress agents: rotenone (ROTR), n-acetyl-L-cysteine, (NACR), or dithiothreitol (DTTR). Resistant cells divided more rapidly and had intracellular homeostatic redox-couple ratios that were shifted towards the reduced state. Resistance caused alterations in general cell morphology, but only ROTR cells had significant changes in mitochondrial morphology with higher numbers that were more isolated, fragmented and swollen, with greater membrane depolarization and decreased numbers of networks. These changes were accompanied by lower basal oxygen consumption and maximal respiration rates. Whole cell flux analyses and mitochondrial function assays showed that NACR and DTTR preferentially utilized tricarboxylic acid (TCA) cycle intermediates, while ROTR used ketone body substrates such as D, L-β-hydroxybutyric acid. NACR and DTTR cells had constitutively decreased levels of reactive oxygen species (ROS), although this was accompanied by activation of nuclear factor erythroid 2-related factor 2 (Nrf2), with concomitant increased expression of the downstream gene products such as glutathione S-transferase P (GSTP). Further adaptations included enhanced expression of endoplasmic reticulum proteins controlling the unfolded protein response (UPR). Although expression patterns of these UPR proteins were distinct between the resistant cells, a trend implied that resistance to reductive stress is accompanied by a constitutively increased UPR phenotype in each line. Overall, tumor cells, although tolerant of oxidative stress, can adapt their energy and survival mechanisms in lethal reductive stress conditions.

Keywords:  Glycolysis; Melanoma cell lines; Mitochondrial morphology; Reactive oxygen species; Reductive stress; Unfolded protein response

DOI:  https://doi.org/10.1016/j.bcp.2023.115929
Nat Commun. 2023 11 18. 14(1): 7525

Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution.

Alon Stern, Mariam Fokra, Boris Sarvin, Ahmad Abed Alrahem, Won Dong Lee, Elina Aizenshtein, Nikita Sarvin, Tomer Shlomi.

The inability to inspect metabolic activities within distinct subcellular compartments has been a major barrier to our understanding of eukaryotic cell metabolism. Previous work addressed this challenge by analyzing metabolism in isolated organelles, which grossly bias metabolic activity. Here, we describe a method for inferring physiological metabolic fluxes and metabolite concentrations in mitochondria and cytosol based on isotope tracing experiments performed with intact cells. This is made possible by computational deconvolution of metabolite isotopic labeling patterns and concentrations into cytosolic and mitochondrial counterparts, coupled with metabolic and thermodynamic modelling. Our approach lowers the uncertainty regarding compartmentalized fluxes and concentrations by one and three orders of magnitude compared to existing modelling approaches, respectively. We derive a quantitative view of mitochondrial and cytosolic metabolic activities in central carbon metabolism across cultured cell lines without performing cell fractionation, finding major variability in compartmentalized malate-aspartate shuttle fluxes. We expect our approach for inferring metabolism at a subcellular resolution to be instrumental for a variety of studies of metabolic dysfunction in human disease and for bioengineering.

DOI: https://doi.org/10.1038/s41467-023-42824-z
Free Radic Biol Med. 2023 Nov 16. pii: S0891-5849(23)01101-2. [Epub ahead of print]

Mitochondrial hyperfusion induces metabolic remodeling in lung endothelial cells by modifying the activities of electron transport chain complexes I and III.

Manivannan Yegambaram, Xutong Sun, Qing Lu, Yan Jin, Wojciech Ornatowski, Jamie Soto, Saurabh Aggarwal, Ting Wang, Kim Tieu, Haiwei Gu, Jeffrey R Fineman, Stephen M Black.

  OBJECTIVE: Pulmonary hypertension (PH) is a progressive disease with vascular remodeling as a critical structural alteration. We have previously shown that metabolic reprogramming is an early initiating mechanism in animal models of PH. This metabolic dysregulation has been linked to remodeling the mitochondrial network to favor fission. However, whether the mitochondrial fission/fusion balance underlies the metabolic reprogramming found early in PH development is unknown.METHODS: Utilizing a rat early model of PH, in conjunction with cultured pulmonary endothelial cells (PECs), we utilized metabolic flux assays, Seahorse Bioassays, measurements of electron transport chain (ETC) complex activity, fluorescent microscopy, and molecular approaches to investigate the link between the disruption of mitochondrial dynamics and the early metabolic changes that occur in PH.
RESULTS: We observed increased fusion mediators, including Mfn1, Mfn2, and Opa1, and unchanged fission mediators, including Drp1 and Fis1, in a two-week monocrotaline-induced PH animal model (early-stage PH). We were able to establish a connection between increases in fusion mediator Mfn1 and metabolic reprogramming. Using an adenoviral expression system to enhance Mfn1 levels in pulmonary endothelial cells and utilizing 13C-glucose labeled substrate, we found increased production of 13C lactate and decreased TCA cycle metabolites, revealing a Warburg phenotype. The use of a 13C5-glutamine substrate showed evidence that hyperfusion also induces oxidative carboxylation. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels secondary to the disruption of cellular bioenergetics and higher levels of mitochondrial reactive oxygen species (mt-ROS). The elevation in mt-ROS correlated with attenuated ETC complexes I and III activities. Utilizing a mitochondrial-targeted antioxidant to suppress mt-ROS, limited HIF-1α protein levels, which reduced cellular glycolysis and reestablished mitochondrial membrane potential.
CONCLUSIONS: Our data connects mitochondrial fusion-mediated mt-ROS to the Warburg phenotype in early-stage PH development.

Keywords:  Glycolysis; Metabolomics; Mitochondrial function; Mitofusin; Pulmonary hypertension

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.11.008
Cancer Discov. 2023 Nov 22. OF1

Vitamin B5 Supports Oncogenic Metabolism in MYC-Driven Breast Cancer.

Pantothetic acid is required for metabolic activity that supports MYC-driven breast tumor growth.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-185
JCI Insight. 2023 Nov 22. pii: e172366. [Epub ahead of print]8(22):

Multiomics of HER2-low triple-negative breast cancer identifies a receptor tyrosine kinase-relevant subgroup with therapeutic prospects.

Lie Chen, Cui-Cui Liu, Si-Yuan Zhu, Jing-Yu Ge, Yu-Fei Chen, Ding Ma, Zhi-Ming Shao, Ke-Da Yu.

  To provide complementary information and reveal the molecular characteristics and therapeutic insights of HER2-low breast cancer, we performed this multiomics study of hormone receptor-negative (HR-) and HER2-low breast cancer, also known as HER2-low triple-negative breast cancer (TNBC), and identified 3 subgroups: basal-like, receptor tyrosine kinase-relevant (TKR), and mesenchymal stem-like. These 3 subgroups had distinct features and potential therapeutic targets and were validated in external data sets. Interestingly, the TKR subgroup (which exists in both HR+ and HR- breast cancer) had activated HER2 and downstream MAPK signaling. In vitro and in vivo patient-derived xenograft experiments revealed that pretreatment of the TKR subgroup with a tyrosine kinase inhibitor (lapatinib or tucatinib) could inhibit HER2 signaling and induce accumulated expression of nonfunctional HER2, resulting in increased sensitivity to the sequential HER2-targeting, Ab-drug conjugate DS-8201. Our findings identify clinically relevant subgroups and provide potential therapeutic strategies for HER2-low TNBC subtypes.

Keywords:  Breast cancer; Oncology

DOI:  https://doi.org/10.1172/jci.insight.172366
Biochem Pharmacol. 2023 Nov 22. pii: S0006-2952(23)00526-9. [Epub ahead of print]219 115933

Ferroptosis resistance in cancer: recent advances and future perspectives.

Xing Zhang, Xiang Li, Ran Xia, Hong-Sheng Zhang.

  Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death and has been implicated in the occurrence and development of various diseases, including heart disease, nervous system diseases and cancer. Ferroptosis induction recently emerged as an attractive strategy for cancer therapy. Ferroptosis has become a potential target for intervention in these diseases or injuries in relevant preclinical models. This review summarizes recent progress on the mechanisms of ferroptosis resistance in cancer, highlights redox status and metabolism's role in it. Combination therapy for ferroptosis has great potential in cancer treatment, especially malignant tumors that are resistant to conventional therapies. This review will lead us to have a comprehensive understanding of the future exploration of ferroptosis and cancer therapy. A deeper understanding of the relationship between ferroptosis resistance and metabolism reprogramming may provide new strategies for tumor treatment and drug development based on ferroptosis.

Keywords:  Cancer therapies; Ferroptosis; Ferroptosis resistance; Metabolism; Programmed cell death

DOI:  https://doi.org/10.1016/j.bcp.2023.115933
Nutrients. 2023 Nov 17. pii: 4807. [Epub ahead of print]15(22):

High Fat Diet-Induced Obesity Dysregulates Splenic B Cell Mitochondrial Activity.

Anandita Pal, Chien-Te Lin, Ilya Boykov, Emily Benson, Grahame Kidd, Kelsey H Fisher-Wellman, P Darrell Neufer, Saame Raza Shaikh.

  Diet-induced obesity impairs mitochondrial respiratory responses in tissues that are highly metabolically active, such as the heart. However, less is known about the impact of obesity on the respiratory activity of specific cell types, such as splenic B cells. B cells are of relevance, as they play functional roles in obesity-induced insulin resistance, inflammation, and responses to infection. Here, we tested the hypothesis that high-fat-diet (HFD)-induced obesity could impair the mitochondrial respiration of intact and permeabilized splenic CD19+ B cells isolated from C57BL/6J mice and activated ex vivo with lipopolysaccharide (LPS). High-resolution respirometry was used with intact and permeabilized cells. To reveal potential mechanistic targets by which HFD-induced obesity dysregulates B cell mitochondria, we conducted proteomic analyses and 3D serial block face scanning electron microscopy (SBFEM). High-resolution respirometry revealed that intact LPS-stimulated B cells of obese mice, relative to controls, displayed lower ATP-linked, as well as maximal uncoupled, respiration. To directly investigate mitochondrial function, we used permeabilized LPS-stimulated B cells, which displayed increased H2O2 emission and production with obesity. We also examined oxidative phosphorylation efficiency simultaneously, which revealed that oxygen consumption and ATP production were decreased in LPS-stimulated B cells with obesity relative to controls. Despite minimal changes in total respiratory complex abundance, in LPS-stimulated B cells of obese mice, three of the top ten most downregulated proteins were all accessory subunits of respiratory complex I. SBFEM showed that B cells of obese mice, compared to controls, underwent no change in mitochondrial cristae integrity but displayed increased mitochondrial volume that was linked to bioenergetic function. Collectively, these results establish a proof of concept that HFD-induced obesity dysregulates the mitochondrial bioenergetic metabolism of activated splenic B cells.

Keywords:  B cells; high fat diet; mitochondria; obesity; proteome

DOI:  https://doi.org/10.3390/nu15224807
Cancers (Basel). 2023 Nov 14. pii: 5409. [Epub ahead of print]15(22):

Treatment of Acute Myeloid Leukemia in Older Adults.

Aseel Alsouqi, Emily Geramita, Annie Im.

  Acute Myeloid Leukemia (AML) is an aggressive myeloid malignancy predominantly affecting older adults. Despite the advancements in new therapies for AML, older and medically unfit patients continue to suffer from poor outcomes due to disease-related factors such as the mutational profile and patient-related factors such as comorbidities and performance status. In this review, we discuss a spectrum of therapeutic options for older patients with AML starting with a historical perspective and ending with therapies being investigated in clinical trials. We review the standard of care treatment options including combination venetoclax and hypomethylating agents, in addition to targeted therapies such as FLT3 and IDH inhibitors. Lastly, we shed light on challenges facing the care of older adults and their representation in clinical trials.

Keywords:  Acute Myeloid Leukemia; older adults; unfit adults

DOI:  https://doi.org/10.3390/cancers15225409
Dev Neurosci. 2023 Nov 17.

Oxidative stress accompanies HIF1-dependent impairment of glucose metabolism in the hippocampus of adult rats survived prenatal severe hypoxia.

Oleg Vetrovoy, Viktor Stratilov, Sofiya Potapova, Ekaterina Tyulkova.

INTRODUCTION: Many socially significant diseases are associated with prenatal developmental disorders. Previously, we showed the pathological role of hypoxia-inducible factor HIF1 in post-hypoxic reoxygenation. This study aimed to investigate the effect of prenatal severe hypoxia (PSH) on HIF1α protein expression as well as on HIF1-dependent activity of the pentose phosphate pathway (PPP) and anaerobic glycolysis in the hippocampus (HPC) of offspring that reached adulthood.METHODS: PSH was induced during the critical period of fetal hippocampal formation on gestation days 14-16 in a hypobaric chamber (180 Torr, 5% oxygen, 3 hours). Subsequent studies were conducted on both the HPC of adult control and PSH rats under normal conditions, as well as in response to severe hypobaric hypoxia (SH) or psycho-emotional stress ("learned helplessness" model, LH). We evaluated HIF1α protein levels using both immunohistochemistry and western blotting techniques. The amount of glucose-6-phosphate dehydrogenase (G6PD) was also determined by western blotting. Colorimetric enzymatic assays were employed to analyze enzymatic activity of lactate dehydrogenase (LDH), the concentration of lactate, NADPH, reduced glutathione (GSHred), and malonic dialdehyde (MDA).
RESULTS: We showed that PSH caused a stable increase in the content of HIF1α protein in the HPC, which was accompanied by an increase in the efficiency of anaerobic glycolysis. This was confirmed by increased LDH activity and lactate concentration. At the same time, the amounts of G6PD, NADPH, and reduced glutathione decreased in the HPC of PSH rats, whereas the concentration of MDA, an oxidative stress marker, exceeded the control values. In a series of experiments using the LH or SH stress, it was shown that in the HPC of control rats, there was an increase in the amount of HIF1α in response to stress, which was also accompanied by more efficient anaerobic glycolysis and decreased of PPP-dependent NADPH production, similar to the intact PSH rats. In PSH rats, emotional stress resulted in higher HIF1α levels without affecting glycolysis or PPP.
CONCLUSION: Therefore, the increased content and activity of the transcription factor HIF1α in the HPC of adult rats exposed to prenatal hypoxia leads to an imbalance between glycolysis and PPP, which is accompanied by oxidative stress.

DOI: https://doi.org/10.1159/000535326
Cell Rep Med. 2023 Nov 21. pii: S2666-3791(23)00484-6. [Epub ahead of print]4(11): 101290

Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML.

Bogdan Popescu, Carlos Stahlhut, Theodore C Tarver, Sydney Wishner, Bianca J Lee, Cheryl A C Peretz, Cuyler Luck, Paul Phojanakong, Juan Antonio Camara Serrano, Henry Hongo, Jose M Rivera, Simayijiang Xirenayi, John A Chukinas, Veronica Steri, Sarah K Tasian, Elliot Stieglitz, Catherine C Smith.

  Mutations in the receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although selective FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report the pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppresses proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that pharmacologic SHP2 inhibition unveils an Achilles' heel of RTK-driven AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.

Keywords:  FLT3; SHP2; acute myeloid leukemia; apoptosis; cancer; drug synergy; targeted therapies

DOI:  https://doi.org/10.1016/j.xcrm.2023.101290
Mol Med Rep. 2024 Jan;pii: 12. [Epub ahead of print]29(1):

The effect of lactate dehydrogenase inhibitors on proliferation, motility and invasion of breast cancer cells in vitro highlights a new role for lactate.

Maitham A Khajah, Sarah Khushaish, Yunus A Luqmani.

  Lactate dehydrogenase (LDH) is being increasingly recognized as a major factor in the progression of breast cancer. It was previously shown that short interfering RNA‑mediated knockdown of either LDH‑A or ‑B isoform resulted in inhibition of cell motility due to reduced lactate levels in the extracellular environment. The aim of the present study was to determine the use of pharmacological LDH inhibitors to reduce aggressive behavior of breast cancer cells. The effect of LDH inhibitors was investigated in both estrogen receptor (ER)+ and ER‑ breast cancer cell lines and in normal breast epithelial cells. Cell proliferation, motility and invasion were measured using MTT, wound healing and cultrex assays, respectively. Changes in several key mediators of mitogenic signaling important in breast cancer cells were determined using western blotting. Treatment with various inhibitors reported to block LDH activity resulted in significant reduction in extracellular lactate level, cell proliferation, motility and invasion. This was associated with changes in the levels of vimentin, E‑cadherin, p38 MAPK, ERK1/2 and AKT. A couple of these inhibitors such as quercetin and lonidamine showed preferential inhibition of cancer cell proliferation compared with normal epithelial cell inhibition. These data extend initial findings, further underlining the importance of lactate as a major factor in breast cancer progression and indicate the practical use of various commercially available LDH inhibitors as promising therapeutic agents to oppose the processes leading to cancer progression.

Keywords:  breast cancer; endocrine resistance; epithelial‑mesenchymal transition; invasion; lactate; lactate dehydrogenase; motility

DOI:  https://doi.org/10.3892/mmr.2023.13135
Nat Neurosci. 2023 Nov 23.

Aerobic glycolysis is the predominant means of glucose metabolism in neuronal somata, which protects against oxidative damage.

Yao Wei, QianQian Miao, Qian Zhang, Shiyu Mao, Mengke Li, Xing Xu, Xian Xia, Ke Wei, Yu Fan, Xinlei Zheng, Yinquan Fang, Meng Mei, Qingyu Zhang, Jianhua Ding, Yi Fan, Ming Lu, Gang Hu.

It is generally thought that under basal conditions, neurons produce ATP mainly through mitochondrial oxidative phosphorylation (OXPHOS), and glycolytic activity only predominates when neurons are activated and need to meet higher energy demands. However, it remains unknown whether there are differences in glucose metabolism between neuronal somata and axon terminals. Here, we demonstrated that neuronal somata perform higher levels of aerobic glycolysis and lower levels of OXPHOS than terminals, both during basal and activated states. We found that the glycolytic enzyme pyruvate kinase 2 (PKM2) is localized predominantly in the somata rather than in the terminals. Deletion of Pkm2 in mice results in a switch from aerobic glycolysis to OXPHOS in neuronal somata, leading to oxidative damage and progressive loss of dopaminergic neurons. Our findings update the conventional view that neurons uniformly use OXPHOS under basal conditions and highlight the important role of somatic aerobic glycolysis in maintaining antioxidant capacity.

DOI: https://doi.org/10.1038/s41593-023-01476-4
Clin Cancer Res. 2023 Nov 20.

Exploiting iron metabolism as a therapeutic vulnerability in glioblastoma.

Ali Nabavizadeh, Stephen J Bagley.

In this CCR Translations, we discuss pharmacological ascorbate as a novel therapeutic for glioblastoma. Aberrant iron metabolism in glioblastoma can be assessed noninvasively by MRI and exploited to potentially improve the efficacy of chemoradiotherapy. We contextualize the study's results and discuss the next steps to further develop this paradigm.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-3027
Nutrients. 2023 Nov 13. pii: 4761. [Epub ahead of print]15(22):

Reducing Dietary Polyunsaturated to Saturated Fatty Acids Ratio Improves Lipid and Glucose Metabolism in Obese Zucker Rats.

Gianfranca Carta, Elisabetta Murru, Giovanna Trinchese, Gina Cavaliere, Claudia Manca, Maria Pina Mollica, Sebastiano Banni.

  We investigated the influence of varying dietary polyunsaturated fatty acid (PUFA)/saturated fatty acids (SFA) ratios on insulin resistance (IR), fatty acid metabolism, N-acylethanolamine (NAE) bioactive metabolite levels, and mitochondrial function in lean and obese Zucker rats in a model designed to study obesity and IR from overnutrition. We provided diets with 7% fat (w/w), with either a low PUFA/SFA ratio of 0.48, predominantly comprising palmitic acid (PA), (diet-PA), or the standard AIN-93G diet with a high PUFA/SFA ratio of 3.66 (control, diet-C) over eight weeks. In obese rats on diet-PA versus diet-C, there were reductions in plasma triglycerides, cholesterol, glucose, insulin concentrations and improved muscle mitochondrial function, inflammatory markers and increased muscle N-oleoylethanolamine (OEA), a bioactive lipid that modulates lipid metabolism and metabolic flexibility. Elevated palmitic acid levels were found exclusively in obese rats, regardless of their diet, implying an endogenous production through de novo lipogenesis rather than from a dietary origin. In conclusion, a reduced dietary PUFA/SFA ratio positively influenced glucose and lipid metabolism without affecting long-term PA tissue concentrations. This likely occurs due to an increase in OEA biosynthesis, improving metabolic flexibility in obese rats. Our results hint at a pivotal role for balanced dietary PA in countering the effects of overnutrition-induced obesity.

Keywords:  N-oleoylethanolamine (OEA); dietary fat; fatty acid metabolism; insulin resistance; mitochondria; obesity

DOI:  https://doi.org/10.3390/nu15224761
Curr Opin Hematol. 2023 Nov 21.

Pediatric acute myeloid leukemia - novel approaches.

Seth E Karol, Gwenaelle Gueguen.

PURPOSE OF REVIEW: Despite higher remission and survival rates than observed in adults, children with acute myeloid leukemia (AML) still suffer unacceptably high rates of treatment failure and late toxicities. Ongoing work aims to improve these long-term outcomes through improvements in the utilization of current therapies, the incorporation of novel chemotherapy agents, and improved use of current or novel cellular and immunotherapeutic approaches. In this review, we highlight recent advances and contextualize them within this evolving landscape.RECENT FINDINGS: Novel agents such as the B-cell lymphoma 2 inhibitor venetoclax and the menin inhibitors have shown promising results with implications for large portions of the pediatric AML population. Older agents are being used in novel combinations (e.g. gemtuzumab ozogamicin) or are expanding into pediatrics after longer use in adults (e.g. Fms-like tyrosine kinase 3 inhibitors). Finally, immunotherapeutic approaches offer new options for patients with high-risk or relapsed disease.
SUMMARY: Recent findings have altered the landscape of pediatric AML therapy with exciting immediate and long-term implications. Ongoing studies may soon define this as standard as well. After many years in which few new therapies have become available for children with AML, recent and upcoming advances may soon dramatically alter the therapeutic landscape.

DOI: https://doi.org/10.1097/MOH.0000000000000795
Apoptosis. 2023 Nov 24.

Cell-specific modulation of mitochondrial respiration and metabolism by the pro-apoptotic Bcl-2 family members Bax and Bak.

Dana Sovilj, Cristina Daniela Kelemen, Sarka Dvorakova, Renata Zobalova, Helena Raabova, Jan Kriska, Zuzana Hermanova, Tomas Knotek, Miroslava Anderova, Pavel Klener, Vlada Filimonenko, Jiri Neuzil, Ladislav Andera.

  Proteins from the Bcl-2 family play an essential role in the regulation of apoptosis. However, they also possess cell death-unrelated activities that are less well understood. This prompted us to study apoptosis-unrelated activities of the Bax and Bak, pro-apoptotic members of the Bcl-2 family. We prepared Bax/Bak-deficient human cancer cells of different origin and found that while respiration in the glioblastoma U87 Bax/Bak-deficient cells was greatly enhanced, respiration of Bax/Bak-deficient B lymphoma HBL-2 cells was slightly suppressed. Bax/Bak-deficient U87 cells also proliferated faster in culture, formed tumours more rapidly in mice, and showed modulation of metabolism with a considerably increased NAD+/NADH ratio. Follow-up analyses documented increased/decreased expression of mitochondria-encoded subunits of respiratory complexes and stabilization/destabilization of the mitochondrial transcription elongation factor TEFM in Bax/Bak-deficient U87 and HBL-2 cells, respectively. TEFM downregulation using shRNAs attenuated mitochondrial respiration in Bax/Bak-deficient U87 as well as in parental HBL-2 cells. We propose that (post)translational regulation of TEFM levels in Bax/Bak-deficient cells modulates levels of subunits of mitochondrial respiratory complexes that, in turn, contribute to respiration and the accompanying changes in metabolism and proliferation in these cells.

Keywords:  Bak; Bax; Cell proliferation; Metabolism; Mitochondrial respiration; TEFM

DOI:  https://doi.org/10.1007/s10495-023-01917-2
Eur J Paediatr Neurol. 2023 Nov 15. pii: S1090-3798(23)00164-2. [Epub ahead of print]48 13-16

Is ketogenic diet a 'precision medicine'? Recent developments and future challenges.

Network for Therapy in Rare Epilepsies (NETRE)

  Recently, precision medicine has attracted much attention in the management of epilepsies, but it remains unclear if the increasingly utilized ketogenic diet approaches can truly be considered precision medicine in all epilepsy treatment. Currently, it is the standard treatment for patients with GLUT1 deficiency and the latest NICE guidelines highlight ketogenic diet as a therapeutic option for multi-drug resistant epilepsy patients. Ketogenic diet is presumed to be a precision medicine tool when applied to the treatment of seizures secondary to GLUT1 transporter deficiency. In contrast, the genetic and epigenetic mechanisms modulated by ketogenic diet and underlying its efficacy in other epilepsy types can only be hypothesized to relate to mechanisms of neuroprotection, neuromodulation, and reduction of neuroinflammation. Early ketogenic diet initiation in well-selected patients, would allow immediate action in the direction of neuroprotection and modulation of neuroinflammation, ensuring higher success rates and lower "cost" to the patient in terms of quality of life and comorbidities. These considerations have fueled an increasing interest in investigating the efficacy, side effects, and adherence to long-term use of the ketogenic diet in epilepsy treatment in large contemporary cohorts, available within the scope of multicentric collaborations, such as the European Network for Therapy in Rare Epilepsies (NETRE). Future directions should involve the use of precision medicine, applied to each patient with the help of "omics", whose use should be expanded and inclusive.

Keywords:  Drug-resistant epilepsy; GLUT-1; Ketogenic diet; Precision medicine; Transcriptomic profile

DOI:  https://doi.org/10.1016/j.ejpn.2023.11.002
Anal Chem. 2023 Nov 21.

Methods for Oxygen Determination in an NMR Bioreactor as a Surrogate Marker for Metabolomic Studies in Living Cell Cultures.

Christian Urzì, Christoph Meyer, Jean-Marc Nuoffer, Peter Vermathen.

Nuclear magnetic resonance (NMR) approaches have been described as a powerful method for measuring oxygen in tissue cultures and body fluids by using relaxation time dependencies of substances on pO2. The present NMR study describes methods to longitudinally monitor global, in situ intracellular, and spatially resolved oxygen tension in culture media and 3D cell cultures using relaxation times of water without the need to use external sensors. 1H NMR measurements of water using a modified inversion recovery pulse scheme were employed for global, i.e., intra- and extracellular oxygen estimation in an NMR-bioreactor. The combination of 1H relaxation time T1 and diffusion measurements of water was employed for in situ cellular oxygen content determination. Spatially selective water relaxation time estimations were used for spatially resolved oxygen quantification along the NMR tube length. The inclusion in a study protocol of the presented techniques for oxygen quantification, as a surrogate marker of oxidative phosphorylation (OXPHOS), provides the possibility to measure mitochondrial respiration and metabolic changes simultaneously.

DOI: https://doi.org/10.1021/acs.analchem.3c02314
Biomed Pharmacother. 2023 Nov 23. pii: S0753-3322(23)01703-1. [Epub ahead of print]169 115905

Preclinical characterization of danatinib as a novel FLT3 inhibitor with excellent efficacy against resistant acute myeloid leukemia.

Shan-Liang Sun, Jia-Zhen Wu, Jing-Jing Wang, Hai Zhou, Chen-Qian Zhang, Zhen-Jiang Tong, Yi-Bo Wang, Jiu-Kai Sha, Qing-Xin Wang, Jia-Chuan Liu, Xin-Rui Zheng, Qing-Qing Li, Meng-Yuan Zhang, Jin Yang, Tian-Hua Wei, Zi-Xuan Wang, Yan-Cheng Yu, Ning Ding, Xue-Jiao Leng, Xin Xue, He-Min Li, Wei-Chen Dai, Xiao-Ying Yin, Ye Yang, Jin-Ao Duan, Nian-Guang Li, Zhi-Hao Shi.

  The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.

Keywords:  Acute Myeloid Leukemia; Danatinib; FLT3; Resistance

DOI:  https://doi.org/10.1016/j.biopha.2023.115905
Nat Commun. 2023 Nov 21. 14(1): 7599

A distinct Acyl-CoA binding protein (ACBP6) shapes tissue plasticity during nutrient adaptation in Drosophila.

Xiaotong Li, Jason Karpac.

Nutrient availability is a major selective force in the evolution of metazoa, and thus plasticity in tissue function and morphology is shaped by adaptive responses to nutrient changes. Utilizing Drosophila, we reveal that distinct calibration of acyl-CoA metabolism, mediated by Acbp6 (Acyl-CoA binding-protein 6), is critical for nutrient-dependent tissue plasticity. Drosophila Acbp6, which arose by evolutionary duplication and binds acyl-CoA to tune acetyl-CoA metabolism, is required for intestinal resizing after nutrient deprivation through activating intestinal stem cell proliferation from quiescence. Disruption of acyl-CoA metabolism by Acbp6 attenuation drives aberrant 'switching' of metabolic networks in intestinal enterocytes during nutrient adaptation, impairing acetyl-CoA metabolism and acetylation amid intestinal resizing. We also identified STAT92e, whose function is influenced by acetyl-CoA levels, as a key regulator of acyl-CoA and nutrient-dependent changes in stem cell activation. These findings define a regulatory mechanism, shaped by acyl-CoA metabolism, that adjusts proliferative homeostasis to coordinately regulate tissue plasticity during nutrient adaptation.

DOI: https://doi.org/10.1038/s41467-023-43362-4
Cell Commun Signal. 2023 Nov 23. 21(1): 337

Targeting ferroptosis in melanoma: cancer therapeutics.

Khatereh Khorsandi, HomaSadat Esfahani, Saeedeh Keyvani- Ghamsari, Parisa Lakhshehei.

  Melanoma is an aggressive kind of skin cancer; its rate has risen rapidly over the past few decades. Melanoma reports for only about 1% of skin cancers but leads to a high majority of skin cancer deaths. Thus, new useful therapeutic approaches are currently required, to state effective treatments to consistently enhance the overall survival rate of melanoma patients. Ferroptosis is a recently identified cell death process, which is different from autophagy, apoptosis, necrosis, and pyroptosis in terms of biochemistry, genetics, and morphology which plays an important role in cancer treatment. Ferroptosis happens mostly by accumulating iron and lipid peroxides in the cell. Recently, studies have revealed that ferroptosis has a key role in the tumor's progression. Especially, inducing ferroptosis in cells can inhibit the tumor cells' growth, leading to back warding tumorigenesis. Here, we outline the ferroptosis characteristics from its basic role in melanoma cancer and mention its possible applications in melanoma cancer treatment. Video Abstract.

Keywords:  Cancer treatment; Cell death; Ferroptosis; Melanoma; Targeted therapy

DOI:  https://doi.org/10.1186/s12964-023-01296-w
Am J Physiol Endocrinol Metab. 2023 Nov 22.

Serine synthesis pathway enzyme PHGDH is critical for muscle cell biomass, anabolic metabolism and mTORC1 signaling.

Sakari Mäntyselkä, Kalle Kolari, Philipp Baumert, Laura Ylä-Outinen, Lauri Kuikka, Suvi Lahtonen, Perttu Permi, Henning Wackerhage, Elina Kalenius, Riikka Kivelä, Juha J Hulmi.

  Cells use glycolytic intermediates for anabolism e.g., via the serine synthesis and pentose phosphate pathways. However, we still understand poorly how these metabolic pathways contribute to skeletal muscle cell biomass generation. The first aim of this study was therefore to identify enzymes that limit protein synthesis, myotube size, and proliferation in skeletal muscle cells. We inhibited key enzymes of glycolysis, the pentose phosphate pathway, and serine synthesis pathway to evaluate their importance in C2C12 myotube protein synthesis. Based on the results of this first screen, we then focused on the serine synthesis pathway enzyme phosphoglycerate dehydrogenase (PHGDH). We used two different PHGDH inhibitors and mouse C2C12 and human primary muscle cells to study the importance and function of the PHGDH. Both myoblasts and myotubes incorporated glucose-derived carbon into proteins, RNA, and lipids and we showed that PHGDH is essential in these processes. PHGDH inhibition decreased protein synthesis, myotube size, and myoblast proliferation without cytotoxic effects. The decreased protein synthesis in response to PHGDH inhibition appears to occur mainly mTORC1 dependently as was evident from experiments with insulin-like growth factor 1 and rapamycin. Further metabolomics analyses revealed that PHGDH inhibition accelerated glycolysis and altered amino acid, nucleotide, and lipid metabolism. Lastly, we found that supplementing an antioxidant and redox modulator N-acetylcysteine partially rescued the decreased protein synthesis and mTORC1 signaling during PHGDH inhibition. The data suggest that PHGDH activity is critical for skeletal muscle cell biomass generation from glucose, and that it regulates protein synthesis and mTORC1 signaling.

Keywords:  Glycolysis; Metabolic reprogramming; Protein synthesis; Warburg effect; mTORC1

DOI:  https://doi.org/10.1152/ajpendo.00151.2023