bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023‒10‒29
fifteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Monocarboxylate Transporter-1 (MCT1)-Mediated Lactate Uptake Protects Pancreatic Adenocarcinoma Cells from Oxidative Stress during Glutamine Scarcity Thereby Promoting Resistance against Inhibitors of Glutamine Metabolism.
  2. ASCT2 is the primary serine transporter in cancer cells.
  3. Improved Photodynamic Therapy Based on Glutaminase Blockage via Tumor Membrane Coated CB-839/IR-780 Nanoparticles.
  4. Research progress of hyperthermia in tumor therapy by influencing metabolic reprogramming of tumor cells.
  5. Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy.
  6. A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer.
  7. G6PD Maintains Redox Homeostasis and Biosynthesis in LKB1-Deficient KRAS-Driven Lung Cancer.
  8. Dissecting the Role of Autophagy-Related Proteins in Cancer Metabolism and Plasticity.
  9. Mitochondrial glutamate transporter SLC25A22 uni-directionally export glutamate for metabolic rewiring in radioresistant glioblastoma.
  10. Cancer stem cells: advances in the glucose, lipid and amino acid metabolism.
  11. Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
  12. Role of Oxidative Stress in Metabolic Reprogramming of Brain Cancer.
  13. Beyond energy and growth: the role of metabolism in developmental signaling, cell behavior and diapause.
  14. Exploiting signaling rewiring in cancer cells with co-existing oncogenic drivers.
  15. Phospholipid metabolic adaptation promotes survival of IDH2 mutant acute myeloid leukemia cells.
  1. Antioxidants (Basel). 2023 Sep 30. pii: 1818. [Epub ahead of print]12(10):
    Monocarboxylate Transporter-1 (MCT1)-Mediated Lactate Uptake Protects Pancreatic Adenocarcinoma Cells from Oxidative Stress during Glutamine Scarcity Thereby Promoting Resistance against Inhibitors of Glutamine Metabolism.
    Nourhane Ammar, Maya Hildebrandt, Claudia Geismann, Christian Röder, Timo Gemoll, Susanne Sebens, Ania Trauzold, Heiner Schäfer.
      Metabolic compartmentalization of stroma-rich tumors, like pancreatic ductal adenocarcinoma (PDAC), greatly contributes to malignancy. This involves cancer cells importing lactate from the microenvironment (reverse Warburg cells) through monocarboxylate transporter-1 (MCT1) along with substantial phenotype alterations. Here, we report that the reverse Warburg phenotype of PDAC cells compensated for the shortage of glutamine as an essential metabolite for redox homeostasis. Thus, oxidative stress caused by glutamine depletion led to an Nrf2-dependent induction of MCT1 expression in pancreatic T3M4 and A818-6 cells. Moreover, greater MCT1 expression was detected in glutamine-scarce regions within tumor tissues from PDAC patients. MCT1-driven lactate uptake supported the neutralization of reactive oxygen species excessively produced under glutamine shortage and the resulting drop in glutathione levels that were restored by the imported lactate. Consequently, PDAC cells showed greater survival and growth under glutamine depletion when utilizing lactate through MCT1. Likewise, the glutamine uptake inhibitor V9302 and glutaminase-1 inhibitor CB839 induced oxidative stress in PDAC cells, along with cell death and cell cycle arrest that were again compensated by MCT1 upregulation and forced lactate uptake. Our findings show a novel mechanism by which PDAC cells adapt their metabolism to glutamine scarcity and by which they develop resistance against anticancer treatments based on glutamine uptake/metabolism inhibition.
    Keywords:  anaplerosis; drug resistance; pancreas; tumor metabolism
    DOI:  https://doi.org/10.3390/antiox12101818
  2. bioRxiv. 2023 Oct 11. pii: 2023.10.09.561530. [Epub ahead of print]
    ASCT2 is the primary serine transporter in cancer cells.
    Kelly O Conger, Christopher Chidley, Mete Emir Ozgurses, Huiping Zhao, Yumi Kim, Svetlana E Semina, Philippa Burns, Vipin Rawat, Ryan Sheldon, Issam Ben-Sahra, Jonna Frasor, Peter K Sorger, Gina M DeNicola, Jonathan L Coloff.
      The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo , others are auxotrophic for serine and therefore reliant on the uptake of exogenous serine. Importantly, however, the transporter(s) that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (coded for by the gene SLC1A5 ) as the primary serine transporter in cancer cells. ASCT2 is well-known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that ERα promotes serine uptake by directly activating SLC1A5 transcription. Together, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target in serine metabolism.
    DOI:  https://doi.org/10.1101/2023.10.09.561530
  3. Small. 2023 Oct 24. e2305174
    Improved Photodynamic Therapy Based on Glutaminase Blockage via Tumor Membrane Coated CB-839/IR-780 Nanoparticles.
    Zhiyan Li, Xianghui Li, Yanjun Lu, Xudong Zhu, Wenxuan Zheng, Kai Chen, Song Liu, Jinhui Wu, Wenxian Guan.
      Photodynamic therapy (PDT) has promising applications. However, the lethal function of reactive oxygen species (ROS) produced during PDT is typically limited. This restriction is induced by oxygen shortage in the tumor microenvironment due to tumor cell hypermetabolism and reductive chemicals overexpression in tumor tissues. Glutamine (Gln) metabolism is crucial for malignancy development and is closely associated with redox. Herein, a novel nanoparticle (NP) named IRCB@M is constructed to boost PDT through dual effects. This NP simultaneously blocks aerobic respiration and inhibits cellular reduced substances by blocking the Gln metabolic pathway. Within the nanocomplex, a photosensitizer (IR-780) and a glutaminase inhibitor (CB-839) are self-assembled and then encapsulated by cancer cell membranes for homologous targeting. The Gln metabolism intervention relieves hypoxia and decreases the levels of nicotinamide adenine dinucleotide phosphate (NADPH) as well as reduced glutathione (GSH) in vitro and in vivo, which are the dual amplification effects on the IR-780-mediated lethal PDT. The antitumor effects against gastric cancer are ultimately evoked in vivo, thus offering a novel concept for enhancing PDT and other ROS-dependent therapeutic approaches.
    Keywords:  glutamine metabolism; glutathione depletion; nanomedicine; photodynamic therapy; tumor hypoxia
    DOI:  https://doi.org/10.1002/smll.202305174
  4. Int J Hyperthermia. 2023 ;40(1): 2270654
    Research progress of hyperthermia in tumor therapy by influencing metabolic reprogramming of tumor cells.
    Yuchuan Yang, Linkuan Huangfu, Huizhen Li, Daoke Yang.
      Cellular metabolic reprogramming is an important feature of malignant tumors. Metabolic reprogramming causes changes in the levels or types of specific metabolites inside and outside the cell, which affects tumorigenesis and progression by influencing gene expression, the cellular state, and the tumor microenvironment. During tumorigenesis, a series of changes in the glucose metabolism, fatty acid metabolism, amino acid metabolism, and cholesterol metabolism of tumor cells occur, which are involved in the process of cellular carcinogenesis and constitute part of the underlying mechanisms of tumor formation. Hyperthermia, as one of the main therapeutic tools for malignant tumors, has obvious effects on tumor cell metabolism. In this paper, we will combine the latest research progress in the field of cellular metabolic reprogramming and focus on the current experimental research and clinical treatment of hyperthermia in cellular metabolic reprogramming to discuss the feasibility of cellular metabolic reprogramming-related mechanisms guiding hyperthermia in malignant tumor treatment, so as to provide more ideas for hyperthermia to treat malignant tumors through the direction of cellular metabolic reprogramming.
    Keywords:  Tumor metabolism; combination therapy; hyperthermia; metabolic reprogramming
    DOI:  https://doi.org/10.1080/02656736.2023.2270654
  5. Metabolites. 2023 Oct 12. pii: 1073. [Epub ahead of print]13(10):
    Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy.
    Koichi Fujisawa, Toshihiko Matsumoto, Naoki Yamamoto, Takahiro Yamasaki, Taro Takami.
      Hepatocellular carcinoma (HCC) is one of the most refractory cancers with a high rate of recurrence. Iron is an essential trace element, and iron chelation has garnered attention as a novel therapeutic strategy for cancer. Since intracellular metabolism is significantly altered by inhibiting various proteins by iron chelation, we investigated combination anticancer therapy targeting metabolic changes that are forcibly modified by iron chelator administration. The deferoxamine (DFO)-resistant cell lines were established by gradually increasing the DFO concentration. Metabolomic analysis was conducted to evaluate the metabolic alterations induced by DFO administration, aiming to elucidate the resistance mechanism in DFO-resistant strains and identify potential novel therapeutic targets. Metabolom analysis of the DFO-resistant Huh7 cells revealed enhanced glycolysis and salvage cycle, alternations in glutamine metabolism, and accumulation of dipeptides. Huh7 cultured in the absence of glutamine showed enhanced sensitivity to DFO, and glutaminase inhibitor (CB839) showed a synergistic effect with DFO. Furthermore, the effect of DFO was enhanced by an autophagy inhibitor (chloroquine) in vitro. DFO-induced metabolic changes are specific targets for the development of efficient anticancer combinatorial therapies using DFO. These findings will be useful for the development of new cancer therapeutics in refractory liver cancer.
    Keywords:  autophagy; autophagy inhibitor; combination therapy; energy metabolisms; glutaminase inhibitor; glutamine; hypoxia; iron chelator; liver cancer; metabolomic analysis
    DOI:  https://doi.org/10.3390/metabo13101073
  6. Cancers (Basel). 2023 Oct 20. pii: 5082. [Epub ahead of print]15(20):
    A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer.
    Xiao-Dan Lyu, Yang Liu, Jia Wang, Yuan-Cheng Wei, Yi Han, Xue Li, Qian Zhang, Zheng-Rui Liu, Zheng-Zheng Li, Jing-Wei Jiang, Hao-Lin Hu, Sheng-Tao Yuan, Li Sun.
      BACKGROUND: The microtubule protein inhibitor C118P shows excellent anti-breast cancer effects. However, the potential targets and mechanisms of C118P in breast cancer remain unknown.METHODS: Real-time cellular analysis (RTCA) was used to detect cell viability. Apoptosis and the cell cycle were detected by flow cytometry. Computer docking simulations, surface plasmon resonance (SPR) technology, and microscale thermophoresis (MST) were conducted to study the interaction between C118P and alanine-serine-cysteine transporter 2 (ASCT2). Seahorse XF technology was used to measure the basal oxygen consumption rate (OCR). The effect of C118P in the adipose microenvironment was explored using a co-culture model of adipocytes and breast cancer cells and mouse cytokine chip.
    RESULTS: C118P inhibited proliferation, potentiated apoptosis, and induced G2/M cell cycle arrest in breast cancer cells. Notably, ASCT2 was validated as a C118P target through reverse docking, SPR, and MST. C118P suppressed glutamine metabolism and mediated autophagy via ASCT2. Similar results were obtained in the adipocyte-breast cancer microenvironment. Adipose-derived interleukin-6 (IL-6) promoted the proliferation of breast cancer cells by enhancing glutamine metabolism via ASCT2. C118P inhibited the upregulation of ASCT2 by inhibiting the effect of IL-6 in co-cultures.
    CONCLUSION: C118P exerts an antitumour effect against breast cancer via the glutamine transporter ASCT2.
    Keywords:  ASCT2; C118P; breast neoplasms; cell proliferation; interleukin-6
    DOI:  https://doi.org/10.3390/cancers15205082
  7. bioRxiv. 2023 Oct 09. pii: 2023.10.06.561131. [Epub ahead of print]
    G6PD Maintains Redox Homeostasis and Biosynthesis in LKB1-Deficient KRAS-Driven Lung Cancer.
    Taijin Lan, Sara Arastu, Samuel Wang, Jarrick Lam, Wenping Wang, Vrushank Bhatt, Eduardo Cararo Lopes, Zhixian Hu, Michael Sun, Xuefei Luo, Jonathan M Ghergurovich, Changlong Li, Xiaoyang Su, Joshua D Rabinowitz, Eileen White, Jessie Yanxiang Guo.
      Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NAPDH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer model, we show that ablation of G6PD significantly suppresses Kras G12D/+ ;Lkb1 -/- (KL) but not Kras G12D/+ ;p53 -/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics revealed that G6PD ablation significantly impaired NADPH generation, redox balance and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation caused p53 activation that suppressed tumor growth. As tumor progressed, G6PD-deficient KL tumors increased an alternative NADPH source, serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.
    DOI:  https://doi.org/10.1101/2023.10.06.561131
  8. Cells. 2023 Oct 19. pii: 2486. [Epub ahead of print]12(20):
    Dissecting the Role of Autophagy-Related Proteins in Cancer Metabolism and Plasticity.
    Liliana Torres-López, Oxana Dobrovinskaya.
      Modulation of autophagy as an anticancer strategy has been widely studied and evaluated in several cell models. However, little attention has been paid to the metabolic changes that occur in a cancer cell when autophagy is inhibited or induced. In this review, we describe how the expression and regulation of various autophagy-related (ATGs) genes and proteins are associated with cancer progression and cancer plasticity. We present a comprehensive review of how deregulation of ATGs affects cancer cell metabolism, where inhibition of autophagy is mainly reflected in the enhancement of the Warburg effect. The importance of metabolic changes, which largely depend on the cancer type and form part of a cancer cell's escape strategy after autophagy modulation, is emphasized. Consequently, pharmacological strategies based on a dual inhibition of metabolic and autophagy pathways emerged and are reviewed critically here.
    Keywords:  Warburg effect; aerobic glycolysis; autophagy; autophagy-related (ATGs) genes/proteins; cancer cell metabolism; cancer plasticity; fatty acid oxidation (FAO); tumor microenvironment
    DOI:  https://doi.org/10.3390/cells12202486
  9. Int J Biol Macromol. 2023 Oct 20. pii: S0141-8130(23)04408-2. [Epub ahead of print] 127511
    Mitochondrial glutamate transporter SLC25A22 uni-directionally export glutamate for metabolic rewiring in radioresistant glioblastoma.
    Eunguk Shin, Byeongsoo Kim, Hyunkoo Kang, Haksoo Lee, Junhyung Park, JiHoon Kang, Eunho Park, Sunmi Jo, Hae Yu Kim, Jung Sub Lee, Jae-Myung Lee, HyeSook Youn, BuHyun Youn.
      Glioblastoma Multiforme (GBM) is a malignant primary brain tumor. Radiotherapy, one of the standard treatments for GBM patients, could induce GBM radioresistance via rewiring cellular metabolism. However, the precise mechanism attributing to GBM radioresistance or targeting strategies to overcome GBM radioresistance are lacking. Here, we demonstrate that SLC25A22, a mitochondrial bi-directional glutamate transporter, is upregulated and showed uni-directionality from mitochondria to cytosol in radioresistant GBM cells, resulting in accumulating cytosolic glutamate. However, mitochondrial glutaminolysis-mediated TCA cycle metabolites and OCR are maintained constantly. The accumulated cytosolic glutamate enhances the glutathione (GSH) production and proline synthesis in radioresistant GBM cells. Increased GSH protects cells against ionizing radiation (IR)-induced reactive oxygen species (ROS) whereas increased proline, a rate-limiting substrate for collagen biosynthesis, induces extracellular matrix (ECM) remodeling, leading to GBM invasive phenotypes. Finally, we discover that genetic inhibition of SLC25A22 using miR-184 mimic decreases GBM radioresistance and aggressiveness both in vitro and in vivo. Collectively, our study suggests that SLC25A22 upregulation confers GBM radioresistance by rewiring glutamate metabolism, and SLC25A22 could be a significant therapeutic target to overcome GBM radioresistance.
    Keywords:  Glioblastoma; Radioresistance; SLC25A22
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.127511
  10. Mol Cell Biochem. 2023 Oct 26.
    Cancer stem cells: advances in the glucose, lipid and amino acid metabolism.
    Weina Kong, Yunge Gao, Shuhua Zhao, Hong Yang.
      Cancer stem cells (CSCs) are a class of cells with self-renewal and multi-directional differentiation potential, which are present in most tumors, particularly in aggressive tumors, and perform a pivotal role in recurrence and metastasis and are expected to be one of the important targets for tumor therapy. Studies of tumor metabolism in recent years have found that the metabolic characteristics of CSCs are distinct from those of differentiated tumor cells, which are unique to CSCs and contribute to the maintenance of the stemness characteristics of CSCs. Moreover, these altered metabolic profiles can drive the transformation between CSCs and non-CSCs, implying that these metabolic alterations are important markers for CSCs to play their biological roles. The identification of metabolic changes in CSCs and their metabolic plasticity mechanisms may provide some new opportunities for tumor therapy. In this paper, we review the metabolism-related mechanisms of CSCs in order to provide a theoretical basis for their potential application in tumor therapy.
    Keywords:  Amino acid metabolism; Cancer stem cell (CSC); Glucose metabolism; Lipid metabolism; Tumor therapy
    DOI:  https://doi.org/10.1007/s11010-023-04861-6
  11. Redox Biol. 2023 Oct 17. pii: S2213-2317(23)00333-6. [Epub ahead of print]67 102932
    Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
    Gerardo G Piroli, Allison M Manuel, Richard S McCain, Holland H Smith, Oliver Ozohanics, Sara Mellid, J Hunter Cox, William E Cotham, Michael D Walla, Alberto Cascón, Attila Ambrus, Norma Frizzell.
      The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the α-ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the affected regions of the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the existing oxidative phosphorylation (OXPHOS) ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.
    Keywords:  Alpha-ketoglutarate dehydrogenase; Complex I; Fumarate; Leigh syndrome; Protein succination; Substrate level phosphorylation
    DOI:  https://doi.org/10.1016/j.redox.2023.102932
  12. Cancers (Basel). 2023 Oct 10. pii: 4920. [Epub ahead of print]15(20):
    Role of Oxidative Stress in Metabolic Reprogramming of Brain Cancer.
    Kirti Agrawal, Shailendra Asthana, Dhruv Kumar.
      Brain cancer is known as one of the deadliest cancers globally. One of the causative factors is the imbalance between oxidative and antioxidant activities in the body, which is referred to as oxidative stress (OS). As part of regular metabolism, oxygen is reduced by electrons, resulting in the creation of numerous reactive oxygen species (ROS). Inflammation is intricately associated with the generation of OS, leading to the increased production and accumulation of reactive oxygen and nitrogen species (RONS). Glioma stands out as one of the most common malignant tumors affecting the central nervous system (CNS), characterized by changes in the redox balance. Brain cancer cells exhibit inherent resistance to most conventional treatments, primarily due to the distinctive tumor microenvironment. Oxidative stress (OS) plays a crucial role in the development of various brain-related malignancies, such as glioblastoma multiforme (GBM) and medulloblastoma, where OS significantly disrupts the normal homeostasis of the brain. In this review, we provide in-depth descriptions of prospective targets and therapeutics, along with an assessment of OS and its impact on brain cancer metabolism. We also discuss targeted therapies.
    Keywords:  RNS; RONS; ROS; brain cancer; oxidative stress; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers15204920
  13. Development. 2023 Oct 15. pii: dev201610. [Epub ahead of print]150(20):
    Beyond energy and growth: the role of metabolism in developmental signaling, cell behavior and diapause.
    Trevor S Tippetts, Matthew H Sieber, Ashley Solmonson.
      Metabolism is crucial for development through supporting cell growth, energy production, establishing cell identity, developmental signaling and pattern formation. In many model systems, development occurs alongside metabolic transitions as cells differentiate and specialize in metabolism that supports new functions. Some cells exhibit metabolic flexibility to circumvent mutations or aberrant signaling, whereas other cell types require specific nutrients for developmental progress. Metabolic gradients and protein modifications enable pattern formation and cell communication. On an organism level, inadequate nutrients or stress can limit germ cell maturation, implantation and maturity through diapause, which slows metabolic activities until embryonic activation under improved environmental conditions.
    Keywords:  Diapause; Embryogenesis; Metabolism; Signaling
    DOI:  https://doi.org/10.1242/dev.201610
  14. Mol Oncol. 2023 Oct 23.
    Exploiting signaling rewiring in cancer cells with co-existing oncogenic drivers.
    Roberto Chiarle, Chiara Ambrogio.
      The development of tailored therapies designed to specifically target driver oncogenes has initiated a revolutionary era in cancer biology. The availability of a growing number of selective inhibitors has generated novel experimental and clinical paradigms. These represent an opportunity and a challenge for researchers and clinicians to delve deeper into the intricate dynamics of cancer development and response to treatment. By directly inhibiting key driver oncogenes involved in tumor initiation and progression, scientists have an unprecedented opportunity to conduct longitudinal and clonal evolutionary studies of how cancer cells adapt, rewire and exploit conflictive or overlapping signaling dependencies in response to treatment in vitro and in vivo. This challenge has to be progressively resolved to discover more effective and personalized cancer therapies.
    Keywords:  Driver oncogenes; Drug resistance; Signaling rewiring
    DOI:  https://doi.org/10.1002/1878-0261.13547
  15. Cancer Sci. 2023 Oct 26.
    Phospholipid metabolic adaptation promotes survival of IDH2 mutant acute myeloid leukemia cells.
    Tatsuya Morishima, Koichi Takahashi, Desmond Wai Loon Chin, Yuxin Wang, Kenji Tokunaga, Yuichiro Arima, Masao Matsuoka, Toshio Suda, Hitoshi Takizawa.
      Genetic mutations in the isocitrate dehydrogenase (IDH) gene that result in a pathological enzymatic activity to produce oncometabolite have been detected in acute myeloid leukemia (AML) patients. While specific inhibitors that target mutant IDH enzymes and normalize intracellular oncometabolite level have been developed, refractoriness and resistance has been reported. Since acquisition of pathological enzymatic activity is accompanied by the abrogation of the crucial WT IDH enzymatic activity in IDH mutant cells, aberrant metabolism in IDH mutant cells can potentially persist even after the normalization of intracellular oncometabolite level. Comparisons of isogenic AML cell lines with and without IDH2 gene mutations revealed two mutually exclusive signalings for growth advantage of IDH2 mutant cells, STAT phosphorylation associated with intracellular oncometabolite level and phospholipid metabolic adaptation. The latter came to light after the oncometabolite normalization and increased the resistance of IDH2 mutant cells to arachidonic acid-mediated apoptosis. The release of this metabolic adaptation by FDA-approved anti-inflammatory drugs targeting the metabolism of arachidonic acid could sensitize IDH2 mutant cells to apoptosis, resulting in their eradication in vitro and in vivo. Our findings will contribute to the development of alternative therapeutic options for IDH2 mutant AML patients who do not tolerate currently available therapies.
    Keywords:  acute myeloid leukemia; apoptosis; arachidonic acid; drug repositioning; phospholipid
    DOI:  https://doi.org/10.1111/cas.15994
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