bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021‒08‒15
23 papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development
  1. Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming.
  2. Dietary polyphenols in chemoprevention and synergistic effect in cancer: Clinical evidences and molecular mechanisms of action.
  3. Ferroptosis: A Trusted Ally in Combating Drug Resistance in Cancer.
  4. Iron Homeostasis and Metabolism: Two Sides of a Coin.
  5. Hyperbaric Oxygen Therapy Represses the Warburg Effect and Epithelial-Mesenchymal Transition in Hypoxic NSCLC Cells via the HIF-1α/PFKP Axis.
  6. A persistent look at how tumours evade therapy.
  7. Deubiquitinase PSMD14 promotes ovarian cancer progression by decreasing enzymatic activity of PKM2.
  8. Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determinant of Tumor Growth and Metastasis.
  9. Acylglycerol Kinase-Targeted Therapies in Oncology.
  10. Harnessing Lactate Metabolism for Radiosensitization.
  11. MTAP deficiency-induced metabolic reprogramming creates a vulnerability to co-targeting de novo purine synthesis and glycolysis in pancreatic cancer.
  12. TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation.
  13. Small Molecule Regulators of Ferroptosis.
  14. NAD+ metabolism controls growth inhibition by HIF1 in normoxia and determines differential sensitivity of normal and cancer cells.
  15. Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters.
  16. A proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies.
  17. Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting.
  18. Histone Methylation Connects DNA Repair to Metabolism in Cancer Cells.
  19. Overcoming Therapeutic Challenges for Pancreatic Ductal Adenocarcinoma with xCT Inhibitors.
  20. Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis.
  21. Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer.
  22. Delivery of a system xc- inhibitor by a redox-responsive levodopa prodrug nanoassembly for combination ferrotherapy.
  23. Pharmacological basis and new insights of taxifolin: A comprehensive review.
  1. Theranostics. 2021 ;11(17): 8322-8336
    Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming.
    Zhenzhen Li, Chanjun Sun, Zhihai Qin.
      Cancer cells are well-known for adapting their metabolism to maintain high proliferation rates and survive in unfavorable environments with low oxygen and nutritional deficiency. Metabolic reprogramming most commonly arises from the tumor microenvironment (TME). The events of metabolic pathways include the Warburg effect, shift in Krebs cycle metabolites, and increase rate of oxidative phosphorylation that provides the energy for the development and invasion of cancer cells. The TME and shift in tumor metabolism shows a close relationship through bidirectional signaling pathways between the stromal and tumor cells. Cancer-associated fibroblasts (CAFs) are the main type of stromal cells in the TME and consist of a heterogeneous and plastic population that play key roles in tumor growth and metastatic capacity. Emerging evidence suggests that CAFs act as major regulators in shaping tumor metabolism especially through the dysregulation of several metabolic pathways, including glucose, amino acid, and lipid metabolism. The arrangement of these metabolic switches is believed to shape distinct CAF behavior and change tumor cell behavior by the CAFs. The crosstalk between cancer cells and CAFs is associated with cell metabolic reprogramming that contributes to cancer cell growth, progression, and evasion from cancer therapies. But the mechanism and process of this interaction remain unclear. This review aimed to highlight the metabolic couplings between tumor cells and CAFs. We reviewed the recent literature supporting an important role of CAFs in the regulation of cancer cell metabolism, and the relevant pathways, which may serve as targets for therapeutic interventions.
    Keywords:  Cancer; Cancer-associated fibroblasts; Metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.7150/thno.62378
  2. Phytomedicine. 2021 Aug 06. pii: S0944-7113(21)00096-9. [Epub ahead of print]90 153554
    Dietary polyphenols in chemoprevention and synergistic effect in cancer: Clinical evidences and molecular mechanisms of action.
    Srimanta Patra, Biswajita Pradhan, Rabindra Nayak, Chhandashree Behera, Surajit Das, Samir Kumar Patra, Thomas Efferth, Mrutyunjay Jena, Sujit Kumar Bhutia.
      BACKGROUND: Epidemiological studies has revealed that a diet rich in fruits and vegetables could lower the risk of certain cancers. In this setting, natural polyphenols are potent anticancer bioactive compounds to overcome the non-target specificity, undesirable cytotoxicity and high cost of treatment cancer chemotherapy.PURPOSE: The review focuses on diverse classifications of the chemical diversity of dietary polyphenol and their molecular targets, modes of action, as well as preclinical and clinical applications in cancer prevention.
    RESULTS: The dietary polyphenols exhibit chemo-preventive activity through modulation of apoptosis, autophagy, cell cycle progression, inflammation, invasion and metastasis. Polyphenols possess strong antioxidant activity and control multiple molecular events through activation of tumor suppressor genes and inhibition of oncogenes involved in carcinogenesis. Numerous in vitro and in vivo studies have evidenced that these dietary phytochemicals regulate critical molecular targets and pathways to limit cancer initiation and progression. Moreover, natural polyphenols act synergistically with existing clinically approved drugs. The improved anticancer activity of combinations of polyphenols and anticancer drugs represents a promising perspective for clinical applications against many human cancers.
    CONCLUSION: The anticancer properties exhibited by dietary polyphenols are mainly attributed to their anti-metastatic, anti-proliferative, anti-angiogenic, anti-inflammatory, cell cycle arrest, apoptotic and autophagic effects. Hence, regular consumption of dietary polyphenols as food or food additives or adjuvants can be a promising tactic to preclude adjournment or cancer therapy.
    Keywords:  Apoptosis; Autophagy; Cancer; Chemoprevention; Polyphenol
    DOI:  https://doi.org/10.1016/j.phymed.2021.153554
  3. Curr Med Chem. 2021 Aug 10.
    Ferroptosis: A Trusted Ally in Combating Drug Resistance in Cancer.
    Erva Ozkan, Filiz Bakar-Ates.
      Ferroptosis, which is an iron-dependent, non-apoptotic cell death mechanism, has recently been proposed as a novel approach in cancer treatment. Bearing distinctive features and its exclusive mechanism have put forward the potential therapeutic benefit of triggering this newly discovered form of cell death. Numerous studies have indicated that apoptotic pathways are often deactivated in resistant cells, leading to a failure in therapy. Hence, alternative strategies to promote cell death are required. Mounting evidence suggests that drug-resistant cancer cells are particularly sensitive to ferroptosis. Given that cancer cells consume a higher amount of iron than healthy ones, ferroptosis not only stands as an excellent alternative to trigger cell death and reverse drug-resistance, but also provides selectivity in therapy. This review focuses specifically on overcoming drug-resistance in cancer through activating ferroptotic pathways and brings together the relevant chemotherapeutics-based and nanotherapeutics-based studies to offer a perspective for researchers regarding the potential use of this mechanism in developing novel therapeutic strategies.
    Keywords:  Cancer; Cisplatin; Erastin; Ferroptosis; Nanotherapeutics; Resistance
    DOI:  https://doi.org/10.2174/0929867328666210810115812
  4. Adv Exp Med Biol. 2021 ;1301 25-40
    Iron Homeostasis and Metabolism: Two Sides of a Coin.
    Vivek Venkataramani.
      Iron is an ancient, essential and versatile transition metal found in almost all living organisms on Earth. This fundamental trace element is used in the synthesis of heme and iron-sulfur (Fe-S) containing proteins and other vital cofactors that are involved in respiration, redox reactions, catalysis, DNA synthesis and transcription. At the same time, the ability of iron to cycle between its oxidized, ferric (Fe3+) and its reduced, ferrous (Fe2+) state contributes to the production of free radicals that can damage biomolecules, including proteins, lipids and DNA. In particular, the regulated non-apoptotic cell death ferroptosis is driven by Fe2+-dependent lipid peroxidation that can be prevented by iron chelation or genetic inhibition of cellular iron uptake. Therefore, iron homeostasis must be tightly regulated to avoid iron toxicity. This review provides an overview of the origin and chemistry of iron that makes it suitable for a variety of biological functions and addresses how organisms evolved various strategies, including their scavenging and antioxidant machinery, to manage redox-associated drawbacks. Finally, key mechanisms of iron metabolism are highlighted in human diseases and model organisms, underlining the perils of dysfunctional iron handlings.
    Keywords:  Fe2+; Fe3+; Ferroptosis; Heme; Iron assimilation; Iron storage; Iron transport; Iron-sulfur-cluster; Lipid peroxidation; Oxidative stress; Reactive oxygen species
    DOI:  https://doi.org/10.1007/978-3-030-62026-4_3
  5. Front Oncol. 2021 ;11 691762
    Hyperbaric Oxygen Therapy Represses the Warburg Effect and Epithelial-Mesenchymal Transition in Hypoxic NSCLC Cells via the HIF-1α/PFKP Axis.
    Linling Zhang, Jingjing Ke, Shengping Min, Nan Wu, Fei Liu, Zhen Qu, Wei Li, Hongtao Wang, Zhongqing Qian, Xiaojing Wang.
      Background: Tumor cells initiate hypoxia-induced mechanisms to fuel cell proliferation, invasion, and metastasis, largely mediated by low O2-responsive Hypoxia-Inducible Factor 1 Alpha (HIF-1α). Therefore, hyperbaric oxygen therapy (HBO) is now being studied in cancer patients, but its impact upon non-small-cell lung cancer (NSCLC) cell metabolism remains uncharacterized.Methods: We employed the NSCLC cell lines A549 and H1299 for in vitro studies. Glucose uptake, pyruvate, lactate, and adenosine triphosphate (ATP) assays were used to assess aerobic glycolysis (Warburg effect). A quantitative glycolytic flux model was used to analyze the flux contributions of HIF-1α-induced glucose metabolism genes. We used a Lewis lung carcinoma (LLC) murine model to measure lung tumorigenesis in C57BL/6J mice.
    Results: HBO suppressed hypoxia-induced HIF-1α expression and downstream HIF-1α signaling in NSCLC cells. One HIF-1α-induced glucose metabolism gene-Phosphofructokinase, Platelet (PFKP)-most profoundly enhanced glycolytic flux under both low- and high-glucose conditions. HBO suppressed hypoxia-induced PFKP transactivation and gene expression via HIF-1α downregulation. HBO's suppression of the Warburg effect, suppression of hyperproliferation, and suppression of epithelial-to-mesenchymal transition (EMT) in hypoxic NSCLC cell lines is mediated by the HIF-1α/PFKP axis. In vivo, HBO therapy inhibited murine LLC lung tumor growth in a Pfkp-dependent manner.
    Conclusions: HBO's repression of the Warburg effect, repression of hyperproliferation, and repression of EMT in hypoxic NSCLC cells is dependent upon HIF-1α downregulation. HIF-1α's target gene PFKP functions as a central mediator of HBO's effects in hypoxic NSCLC cells and may represent a metabolic vulnerability in NSCLC tumors.
    Keywords:  HBO; HIF-1; NSCLC; Warburg effect; hyperbaric oxygen; lung cancer
    DOI:  https://doi.org/10.3389/fonc.2021.691762
  6. Nature. 2021 Aug 11.
    A persistent look at how tumours evade therapy.
    Karen Gomez, Raul Rabadan.
      
    Keywords:  Cancer; Medical research; Metabolism
    DOI:  https://doi.org/10.1038/d41586-021-02117-1
  7. Mol Oncol. 2021 Aug 11.
    Deubiquitinase PSMD14 promotes ovarian cancer progression by decreasing enzymatic activity of PKM2.
    Tianshui Sun, Zhuonan Liu, Fangfang Bi, Qing Yang.
      Dysregulation of deubiquitination has been reported to contribute to carcinogenesis. However, the function and mechanism of deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) in the progression of ovarian cancer (OV), the deadliest gynecological cancer, still remains to be characterized. The present study demonstrated that PSMD14 was overexpressed in OV tissues and its higher levels correlated with a higher International Federation of Gynecology and Obstetrics (FIGO) stage in OV patients. A high level of PSMD14 expression was related to poor survival in OV patients. Knockdown and overexpression experiments elucidated that PSMD14 stimulated OV cell proliferation, invasion and migration in vitro. Repression of PSMD14 suppressed OV tumor growth in vivo. PSMD14 inhibitor O-phenanthroline (OPA) effectively attenuated malignant behaviors of OV cells in vitro and OV tumor growth in vivo. Mechanistically, we uncovered that PSMD14 was involved in post-translational regulation of pyruvate kinase M2 isoform (PKM2). PSMD14 decreased K63-linked ubiquitination on PKM2, downregulated the ratio of PKM2 tetramers to dimers and monomers, and subsequently diminished pyruvate kinase activity and induced nuclear translocation of PKM2, contributing to aerobic glycolysis in OV cells. Collectively, our findings highlight the potential roles of PSMD14 as a biomarker and therapeutic candidate for OV.
    Keywords:  OPA; PKM2; PSMD14; cancer metabolism; deubiquitination
    DOI:  https://doi.org/10.1002/1878-0261.13076
  8. Front Oncol. 2021 ;11 698951
    Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determinant of Tumor Growth and Metastasis.
    Leenu Reinsalu, Marju Puurand, Vladimir Chekulayev, Sten Miller, Igor Shevchuk, Kersti Tepp, Egle Rebane-Klemm, Natalja Timohhina, Anton Terasmaa, Tuuli Kaambre.
      Metabolic plasticity is the ability of the cell to adjust its metabolism to changes in environmental conditions. Increased metabolic plasticity is a defining characteristic of cancer cells, which gives them the advantage of survival and a higher proliferative capacity. Here we review some functional features of metabolic plasticity of colorectal cancer cells (CRC). Metabolic plasticity is characterized by changes in adenine nucleotide transport across the outer mitochondrial membrane. Voltage-dependent anion channel (VDAC) is the main protein involved in the transport of adenine nucleotides, and its regulation is impaired in CRC cells. Apparent affinity for ADP is a functional parameter that characterizes VDAC permeability and provides an integrated assessment of cell metabolic state. VDAC permeability can be adjusted via its interactions with other proteins, such as hexokinase and tubulin. Also, the redox conditions inside a cancer cell may alter VDAC function, resulting in enhanced metabolic plasticity. In addition, a cancer cell shows reprogrammed energy transfer circuits such as adenylate kinase (AK) and creatine kinase (CK) pathway. Knowledge of the mechanism of metabolic plasticity will improve our understanding of colorectal carcinogenesis.
    Keywords:  VDAC; adenylate kinase; aerobic glycolysis; creatine kinase; mitochondria; oxidative phosphorylation; tumor energy metabolism
    DOI:  https://doi.org/10.3389/fonc.2021.698951
  9. Front Cell Dev Biol. 2021 ;9 659158
    Acylglycerol Kinase-Targeted Therapies in Oncology.
    Binxiang Chu, Zhenghua Hong, Xiaohe Zheng.
      Acylglycerol kinase (AGK) is a recently discovered mitochondrial lipid kinase, and mutation of its gene is the fundamental cause of Sengers syndrome. AGK is not only involved in the stability of lipid metabolism but also closely related to mitochondrial protein transport, glycolysis, and thrombocytopoiesis. Evidence indicates that AGK is an important factor in the occurrence and development of tumors. Specifically, AGK has been identified as an oncogene that partakes in the regulation of tumor cell growth, invasion, metastasis, and drug resistance. The versatility of AGK and its unique role in different types of cancerous and normal cells greatly piqued our interest. We believe that AGK is a promising target for cancer therapy. Therefore, this review summarizes the main research advances concerning AGK, including the discovery of its physiological/pathogenic mechanisms, and provides a reference for the feasible evaluation of AGK as a therapeutic target for human diseases, particularly tumors.
    Keywords:  Sengers syndrome; acylglycerol kinase; metabolism; mitochondria; oncogenesis
    DOI:  https://doi.org/10.3389/fcell.2021.659158
  10. Front Oncol. 2021 ;11 672339
    Harnessing Lactate Metabolism for Radiosensitization.
    Kevin X Liu, Emily Everdell, Sharmistha Pal, Daphne A Haas-Kogan, Michael G Milligan.
      Cancer cells rewire their metabolism to promote cell proliferation, invasion, and metastasis. Alterations in the lactate pathway have been characterized in diverse cancers, correlate with outcomes, and lead to many downstream effects, including decreasing oxidative stress, promoting an immunosuppressive tumor microenvironment, lipid synthesis, and building chemo- or radio-resistance. Radiotherapy is a key modality of treatment for many cancers and approximately 50% of patients with cancer will receive radiation for cure or palliation; thus, overcoming radio-resistance is important for improving outcomes. Growing research suggests that important molecular controls of the lactate pathway may serve as novel therapeutic targets and in particular, radiosensitizers. In this mini-review, we will provide an overview of lactate metabolism in cancer, discuss three important contributors to lactate metabolism (lactate dehydrogenase, monocarboxylate transporters, and mitochondrial pyruvate carrier), and present data that inhibition of these three pathways can lead to radiosensitization. Future research is needed to further understand critical regulators of lactate metabolism and explore clinical safety and efficacy of inhibitors of lactate dehydrogenase, monocarboxylate transporters, and mitochondrial pyruvate carrier alone and in combination with radiation.
    Keywords:  Warburg phenomenon; lactate metabolism; radiation therapy; radiosensitization; synergistic effects
    DOI:  https://doi.org/10.3389/fonc.2021.672339
  11. Cancer Res. 2021 Aug 12. pii: canres.0414.2020. [Epub ahead of print]
    MTAP deficiency-induced metabolic reprogramming creates a vulnerability to co-targeting de novo purine synthesis and glycolysis in pancreatic cancer.
    Qiangsheng Hu, Yi Qin, Shunrong Ji, Xiuhui Shi, Weixing Dai, Guixiong Fan, Shuo Li, Wenyan Xu, Wensheng Liu, Mengqi Liu, Zheng Zhang, Zeng Ye, Zhijun Zhou, Jingxuan Yang, Qifeng Zhuo, Xianjun Yu, Min Li, Xiaowu Xu.
      Methylthioadenosine phosphorylase (MTAP) is a key enzyme associated with the salvage of methionine and adenine that is deficient in 20%-30% of pancreatic cancer. Our previous study revealed that MTAP-deficiency indicates a poor prognosis for pancreatic ductal adenocarcinoma (PDAC) patients. In this study, bioinformatics analysis of The Cancer Genome Atlas (TCGA) data indicated that PDACs with MTAP deficiency display a signature of elevated glycolysis. Metabolomics studies showed that that MTAP deletion-mediated metabolic reprogramming enhanced glycolysis and de novo purine synthesis in pancreatic cancer cells. Western blot analysis revealed that MTAP knockout stabilized hypoxia-inducible factor 1α (HIF-1α) protein via posttranslational phosphorylation. RIO kinase 1 (RIOK1), a downstream kinase upregulated in MTAP-deficient cells, interacted with and phosphorylated HIF-1α to regulate its stability. In vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) and the de novo purine synthesis inhibitor L-alanosine synergized to kill MTAP-deficient pancreatic cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0414
  12. FASEB J. 2021 Sep;35(9): e21814
    TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation.
    Payel Mondal, Shrikanth S Gadad, Swagata Adhikari, Enrique I Ramos, Sabyasachi Sen, Parash Prasad, Chandrima Das.
      Alteration in glucose homeostasis during cancer metabolism is an important phenomenon. Though several important transcription factors have been well studied in the context of the regulation of metabolic gene expression, the role of epigenetic readers in this regard remains still elusive. Epigenetic reader protein transcription factor 19 (TCF19) has been recently identified as a novel glucose and insulin-responsive factor that modulates histone posttranslational modifications to regulate glucose homeostasis in hepatocytes. Here we report that TCF19 interacts with a non-histone, well-known tumor suppressor protein 53 (p53) and co-regulates a wide array of metabolic genes. Among these, the p53-responsive carbohydrate metabolic genes Tp53-induced glycolysis and apoptosis regulator (TIGAR) and Cytochrome C Oxidase assembly protein 2 (SCO2), which are the key regulators of glycolysis and oxidative phosphorylation respectively, are under direct regulation of TCF19. Remarkably, TCF19 can form different transcription activation/repression complexes which show substantial overlap with that of p53, depending on glucose-mediated variant stress situations as obtained from IP/MS studies. Interestingly, we observed that TCF19/p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short-term high glucose or prolonged high glucose conditions. TCF19 or p53 knockdown significantly altered the cellular lactate production and led to increased extracellular acidification rate. Similarly, OCR and cellular ATP production were reduced and mitochondrial membrane potential was compromised upon depletion of TCF19 or p53. Subsequently, through RNA-Seq analysis from patients with hepatocellular carcinoma, we observed that TCF19/p53-mediated metabolic regulation is fundamental for sustenance of cancer cells. Together the study proposes that TCF19/p53 complexes can regulate metabolic gene expression programs responsible for mitochondrial energy homeostasis and stress adaptation.
    Keywords:  epigenetics; glucose-mediated stress; metabolism; mitochondrial energy homeostasis; transcription
    DOI:  https://doi.org/10.1096/fj.202002486RR
  13. Adv Exp Med Biol. 2021 ;1301 81-121
    Small Molecule Regulators of Ferroptosis.
    Sylvain Debieu, Stéphanie Solier, Ludovic Colombeau, Antoine Versini, Fabien Sindikubwabo, Alison Forrester, Sebastian Müller, Tatiana Cañeque, Raphaël Rodriguez.
      Ferroptosis is a dedicated mode of cell death involving iron, reactive oxygen species and lipid peroxidation. Involved in processes such as glutathione metabolism, lysosomal iron retention or interference with lipid metabolism, leading either to activation or inhibition of ferroptosis. Given the implications of ferroptosis in diseases such as cancer, aging, Alzheimer and infectious diseases, new molecular mechanisms underlying ferroptosis and small molecules regulators that target those mechanisms have prompted a great deal of interest. Here, we discuss the current scenario of small molecules modulating ferroptosis and critically assess what is known about their mechanisms of action.
    Keywords:  Fenton reaction; Iron; Lipid peroxidation; Reactive oxygen species; Small molecule
    DOI:  https://doi.org/10.1007/978-3-030-62026-4_6
  14. Cell Cycle. 2021 Aug 12. 1-16
    NAD+ metabolism controls growth inhibition by HIF1 in normoxia and determines differential sensitivity of normal and cancer cells.
    Michal W Luczak, Casey Krawic, Anatoly Zhitkovich.
      The hypoxia-induced transcription factor HIF1 inhibits cell growth in normoxia through poorly understood mechanisms. A constitutive upregulation of hypoxia response is associated with increased malignancy, indicating a loss of antiproliferative effects of HIF1 in cancer cells. To understand these differences, we examined a control of cell cycle in primary human cells with activated hypoxia response in normoxia. Activated HIF1 caused a global slowdown of cell cycle progression through G1, S and G2 phases leading to the loss of mitotic cells. Cell cycle inhibition required a prolonged HIF1 activation and was not associated with upregulation of p53 or the CDK inhibitors p16, p21 or p27. Growth inhibition by HIF1 was independent of its Asn803 hydroxylation or the presence of HIF2. Antiproliferative effects of hypoxia response were alleviated by inhibition of lactate dehydrogenase and more effectively, by boosting cellular production of NAD+, which was decreased by HIF1 activation. In comparison to normal cells, various cancer lines showed several fold-higher expression of NAMPT which is a rate-limiting enzyme in the main biosynthetic pathway for NAD+. Inhibition of NAMPT activity in overexpressor cancer cells sensitized them to antigrowth effects of HIF1. Thus, metabolic changes in cancer cells, such as enhanced NAD+ production, create resistance to growth-inhibitory activity of HIF1 permitting manifestation of its tumor-promoting properties.AbbreviationsDMOG: dimethyloxalylglycine, DM-NOFD: dimethyl N-oxalyl-D-phenylalanine, NMN: β-nicotinamide mononucleotide.
    Keywords:  HIF1A; NAD+; NAMPT; cell cycle; hypoxia
    DOI:  https://doi.org/10.1080/15384101.2021.1959988
  15. Nat Commun. 2021 08 12. 12(1): 4905
    Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters.
    Seth J Parker, Joel Encarnación-Rosado, Kate E R Hollinshead, David M Hollinshead, Leonard J Ash, Juan A K Rossi, Elaine Y Lin, Albert S W Sohn, Mark R Philips, Drew R Jones, Alec C Kimmelman.
      α-ketoglutarate (KG), also referred to as 2-oxoglutarate, is a key intermediate of cellular metabolism with pleiotropic functions. Cell-permeable esterified analogs are widely used to study how KG fuels bioenergetic and amino acid metabolism and DNA, RNA, and protein hydroxylation reactions, as cellular membranes are thought to be impermeable to KG. Here we show that esterified KG analogs rapidly hydrolyze in aqueous media, yielding KG that, in contrast to prevailing assumptions, imports into many cell lines. Esterified KG analogs exhibit spurious KG-independent effects on cellular metabolism, including extracellular acidification, arising from rapid hydrolysis and de-protonation of α-ketoesters, and significant analog-specific inhibitory effects on glycolysis or mitochondrial respiration. We observe that imported KG decarboxylates to succinate in the cytosol and contributes minimally to mitochondrial metabolism in many cell lines cultured in normal conditions. These findings demonstrate that nuclear and cytosolic KG-dependent reactions may derive KG from functionally distinct subcellular pools and sources.
    DOI:  https://doi.org/10.1038/s41467-021-25228-9
  16. Mol Cell. 2021 Jul 30. pii: S1097-2765(21)00590-6. [Epub ahead of print]
    A proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies.
    Zhiwei Liu, Yingluo Liu, Lili Qian, Shangwen Jiang, Xiameng Gai, Shu Ye, Yuehong Chen, Xiaomin Wang, Linhui Zhai, Jun Xu, Congying Pu, Jing Li, Fuchu He, Min Huang, Minjia Tan.
      KRAS mutant cancer, characterized by the activation of a plethora of phosphorylation signaling pathways, remains a major challenge for cancer therapy. Despite recent advancements, a comprehensive profile of the proteome and phosphoproteome is lacking. This study provides a proteomic and phosphoproteomic landscape of 43 KRAS mutant cancer cell lines across different tissue origins. By integrating transcriptomics, proteomics, and phosphoproteomics, we identify three subsets with distinct biological, clinical, and therapeutic characteristics. The integrative analysis of phosphoproteome and drug sensitivity information facilitates the identification of a set of drug combinations with therapeutic potentials. Among them, we demonstrate that the combination of DOT1L and SHP2 inhibitors is an effective treatment specific for subset 2 of KRAS mutant cancers, corresponding to a set of TCGA clinical tumors with the poorest prognosis. Together, this study provides a resource to better understand KRAS mutant cancer heterogeneity and identify new therapeutic possibilities.
    Keywords:  DOT1L; KRAS mutation; SHP2; cancer; drug sensitivity; heterogeneity; phosphoproteomics; proteomics; subtype; therapy
    DOI:  https://doi.org/10.1016/j.molcel.2021.07.021
  17. J Exp Clin Cancer Res. 2021 Aug 07. 40(1): 248
    Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting.
    Beatrice Parma, Vignesh Ramesh, Paradesi Naidu Gollavilli, Aarif Siddiqui, Luisa Pinna, Annemarie Schwab, Sabine Marschall, Shuman Zhang, Christian Pilarsky, Francesca Napoli, Marco Volante, Sophia Urbanczyk, Dirk Mielenz, Henrik Daa Schrøder, Marc Stemmler, Heiko Wurdak, Paolo Ceppi.
      BACKGROUND: The identification of novel targets is of paramount importance to develop more effective drugs and improve the treatment of non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths worldwide. Since cells alter their metabolic rewiring during tumorigenesis and along cancer progression, targeting key metabolic players and metabolism-associated proteins represents a valuable approach with a high therapeutic potential. Metabolic fitness relies on the functionality of heat shock proteins (HSPs), molecular chaperones that facilitate the correct folding of metabolism enzymes and their assembly in macromolecular structures.METHODS: Gene fitness was determined by bioinformatics analysis from available datasets from genetic screenings. HSPD1 expression was evaluated by immunohistochemistry from formalin-fixed paraffin-embedded tissues from NSCLC patients. Real-time proliferation assays with and without cytotoxicity reagents, colony formation assays and cell cycle analyses were used to monitor growth and drug sensitivity of different NSCLC cells in vitro. In vivo growth was monitored with subcutaneous injections in immune-deficient mice. Cell metabolic activity was analyzed through extracellular metabolic flux analysis. Specific knockouts were introduced by CRISPR/Cas9.
    RESULTS: We show heat shock protein family D member 1 (HSPD1 or HSP60) as a survival gene ubiquitously expressed in NSCLC and associated with poor patients' prognosis. HSPD1 knockdown or its chemical disruption by the small molecule KHS101 induces a drastic breakdown of oxidative phosphorylation, and suppresses cell proliferation both in vitro and in vivo. By combining drug profiling with transcriptomics and through a whole-genome CRISPR/Cas9 screen, we demonstrate that HSPD1-targeted anti-cancer effects are dependent on oxidative phosphorylation and validated molecular determinants of KHS101 sensitivity, in particular, the creatine-transporter SLC6A8 and the subunit of the cytochrome c oxidase complex COX5B.
    CONCLUSIONS: These results highlight mitochondrial metabolism as an attractive target and HSPD1 as a potential theranostic marker for developing therapies to combat NSCLC.
    Keywords:  HSPD1; KHS101; Metabolism; Non-small cell lung cancer; Targeting
    DOI:  https://doi.org/10.1186/s13046-021-02049-8
  18. Cancer Discov. 2020 Aug;10(8): OF7
    Histone Methylation Connects DNA Repair to Metabolism in Cancer Cells.
      Metabolites produced in cancer cells interfered with resolution of DNA double-strand breaks.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-089
  19. Adv Exp Med Biol. 2021 ;1301 7-24
    Overcoming Therapeutic Challenges for Pancreatic Ductal Adenocarcinoma with xCT Inhibitors.
    Milica Vucetic, Boutaina Daher, Shamir Cassim, Scott Parks, Jacques Pouyssegur.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with a dismal 5-year survival rate of 5% and very limited efficacy of the current therapeutic regimens. The lethality of PDAC stems from asymptomatic early stage of the disease, its propensity to rapidly disseminate, as well as unusual, dense and highly active surrounding stroma. Fortunately, promising literature data suggests that exploiting newly contextualized type of cell death, termed "ferroptosis", has great potential for overcoming the major problems regarding PDAC treatment. A major player in this type of cell death is Glutamate/Cystine antiporter - xCT, which is responsible for the uptake of oxidized form of cysteine, and thus maintenance of intracellular amino acid and redox homeostasis. xCT seems to fulfill all requirements of the solid and specific molecular target for ferroptosis-based anti-cancer therapy. In this chapter we summarized mounting literature data supporting this hypothesis, but also, we pointed out some of the underexamined aspects of xCT-dependent (patho)physiology of the cancer cell, which have to be addressed in future studies. The abstract could be used as "informative abstract" for the online version.
    Keywords:  Cysteine; EMT; Erastin; Ferroptosis; GPx4; GSH; Glutamate/Cystine antiporter; PDAC; xCT
    DOI:  https://doi.org/10.1007/978-3-030-62026-4_2
  20. Nat Commun. 2021 08 10. 12(1): 4814
    Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis.
    Clément Bodineau, Mercedes Tomé, Sarah Courtois, Ana S H Costa, Marco Sciacovelli, Benoit Rousseau, Elodie Richard, Pierre Vacher, Carlos Parejo-Pérez, Emilie Bessede, Christine Varon, Pierre Soubeyran, Christian Frezza, Piedad Del Socorro Murdoch, Victor H Villar, Raúl V Durán.
      Glutamoptosis is the induction of apoptotic cell death as a consequence of the aberrant activation of glutaminolysis and mTORC1 signaling during nutritional imbalance in proliferating cells. The role of the bioenergetic sensor AMPK during glutamoptosis is not defined yet. Here, we show that AMPK reactivation blocks both the glutamine-dependent activation of mTORC1 and glutamoptosis in vitro and in vivo. We also show that glutamine is used for asparagine synthesis and the GABA shunt to produce ATP and to inhibit AMPK, independently of glutaminolysis. Overall, our results indicate that glutamine metabolism is connected with mTORC1 activation through two parallel pathways: an acute alpha-ketoglutarate-dependent pathway; and a secondary ATP/AMPK-dependent pathway. This dual metabolic connection between glutamine and mTORC1 must be considered for the future design of therapeutic strategies to prevent cell growth in diseases such as cancer.
    DOI:  https://doi.org/10.1038/s41467-021-25079-4
  21. EMBO Mol Med. 2021 Aug 08. e13193
    Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer.
    Zhang Yang, Shun-Qing Liang, Maria Saliakoura, Haitang Yang, Eric Vassella, Georgia Konstantinidou, Mario Tschan, Balazs Hegedüs, Liang Zhao, Yanyun Gao, Duo Xu, Haibin Deng, Thomas M Marti, Gregor J Kocher, Wenxiang Wang, Ralph A Schmid, Ren-Wang Peng.
      KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS-driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo-like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS-mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance anti-proliferative effects and cell death in KRAS-mutant lung and pancreatic but not colon nor KRAS wild-type cancer cells. Mechanistically, co-targeting FGFR1 and PLK1 upregulates reactive oxygen species (ROS), leading to oxidative stress-activated c-Jun N-terminal kinase (JNK)/p38 pathway and E2F1-induced apoptosis. We further delineate that autophagy protects from PLK1/FGFR1 inhibitor cytotoxicity and that antagonizing the compensation mechanism by clinically approved chloroquine fully realizes the therapeutic potential of PLK1 and FGFR1 targeting therapy, producing potent and durable responses in KRAS-mutant patient-derived xenografts and a genetically engineered mouse model of Kras-induced lung adenocarcinoma. These results suggest a previously unappreciated role for FGFR1 and PLK1 in the surveillance of metabolic stress and demonstrate a synergistic drug combination for treating KRAS-mutant cancer.
    Keywords:  KRAS-mutant cancer; autophagy; fibroblast growth factor receptor 1; polo-like kinase 1; synthetic lethal vulnerability
    DOI:  https://doi.org/10.15252/emmm.202013193
  22. J Mater Chem B. 2021 Aug 09.
    Delivery of a system xc- inhibitor by a redox-responsive levodopa prodrug nanoassembly for combination ferrotherapy.
    Huhu Xin, Yong Huang, Honglin Tang, Yuan Chen, Hongguang Xia, Fu Zhang, Bowen Li, Yuan Ping.
      A comprehensive understanding of ferroptosis signaling pathways significantly contributes to the advances in cancer ferrotherapy. Herein, we constructed a self-assembled prodrug nanosystem targeting system xc-, a key regulator for ferroptosis, to amplify the therapeutic efficacy of cancer ferrotherapy. The prodrug nanosystem is assembled between sulfasalazine (SSZ, a ferroptosis resistance inhibitor) and disulfide-bridged levodopa (DSSD) that can chelate Fe2+ ions to form SSZ-Fe2+@DSSD, and the resulting nanoassembly can not only inhibit ferroptosis resistance, but also generate ROS in the tumor microenvironment. Whereas the prodrug nanosystem is stable in the physiological environment, it becomes unstable in the tumoral and intracellular reductive microenvironment, where the disulfide linkers are disrupted by high levels of glutathione (GSH), triggering the release of active Fe2+ and SSZ. Under the Fenton reaction, the released Fe2+ thus can induce ferroptosis, which is amplified by SSZ-mediated inhibition of ferroptosis resistance to synergistically improve the therapeutic efficacy of ferroptosis. Our study thus provides an innovative prodrug strategy to advance anticancer ferroptosis.
    DOI:  https://doi.org/10.1039/d1tb00742d
  23. Biomed Pharmacother. 2021 Aug 10. pii: S0753-3322(21)00787-3. [Epub ahead of print]142 112004
    Pharmacological basis and new insights of taxifolin: A comprehensive review.
    Abhijit Das, Ratna Baidya, Tania Chakraborty, Akash Kumar Samanta, Souvik Roy.
      The pharmacological characteristics of phytochemicals have prompted a lot of interest in their application in disease management. Due to the high incidence of cancer related mortality and morbidity throughout the world; experiments have concentrated on identifying the anticancer potential of natural substances. Many phytochemicals such as flavonoids and their derivatives produced from food offer a variety of new anti-cancer agents which prevent the cancer progression. Taxifolin, a unique bioactive flavonoid, is a dietary component that has grabbed the interest of dietitians and medicinal chemists due to its wide range of health benefits. It is a powerful antioxidant with a well-documented effect in the prevention of several malignancies in humans. Taxifolin has shown promising inhibitory activity against inflammation, malignancies, microbial infection, oxidative stress, cardiovascular disease, and liver disease. Anti-cancer activity has been shown to be relatively significant than other activities investigated in vitro and in vivo with a little or no side effects to the normal healthy cells. In summary this review offers the synopsis of recent breakthroughs in the use of taxifolin as a cancer treatment, as well as mechanisms of action. However, to develop a medicine for human usage, more study on pharmacokinetic profile, profound molecular mechanisms, and drug safety criteria should be conducted utilizing well-designed randomized clinical trials.
    Keywords:  Anti-inflammation; Antioxidant; Chemotherapeutics; Flavonoids; Phytochemical; Taxifolin
    DOI:  https://doi.org/10.1016/j.biopha.2021.112004
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