bims-glucam 2021-05-16 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021‒05‒16
eleven papers selected by
Sreeparna Banerjee
Middle East Technical University

Biological Roles and Therapeutic Applications of IDH2 Mutations in Human Cancer.
Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer.
The Warburg Effect: Historical Dogma Versus Current Rationale.
Molecular basis for the allosteric activation mechanism of the heterodimeric imidazole glycerol phosphate synthase complex.
Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation.
Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism.
Autophagy is critical for cysteine metabolism in pancreatic cancer through regulation of SLC7A11.
Metabolic reprogramming in renal cancer: Events of a metabolic disease.
ArfGAP1 inhibits mTORC1 lysosomal localization and activation.
Glutathione-Depleting Nanomedicines for Synergistic Cancer Therapy.
Metabolomics in cancer research and emerging applications in clinical oncology.

Front Oncol. 2021 ;11 644857

Biological Roles and Therapeutic Applications of IDH2 Mutations in Human Cancer.

Jinxiu Guo, Ruyue Zhang, Zhe Yang, Zhenfeng Duan, Detao Yin, Yubing Zhou.

  Isocitrate dehydrogenase (IDH) is a key metabolic enzyme catalyzing the interconversion of isocitrate to α-ketoglutarate (α-KG). Mutations in IDH lead to loss of normal enzymatic activity and gain of neomorphic activity that irreversibly converts α-KG to 2-hydroxyglutarate (2-HG), which can competitively inhibit a-KG-dependent enzymes, subsequently induces cell metabolic reprograming, inhibits cell differentiation, and initiates cell tumorigenesis. Encouragingly, this phenomenon can be reversed by specific small molecule inhibitors of IDH mutation. At present, small molecular inhibitors of IDH1 and IDH2 mutant have been developed, and promising progress has been made in preclinical and clinical development, showing encouraging results in patients with IDH2 mutant cancers. This review will focus on the biological roles of IDH2 mutation in tumorigenesis, and provide a proof-of-principle for the development and application of IDH2 mutant inhibitors for human cancer treatment.

Keywords:  2-HG; IDH2 inhibitors; IDH2 mutation; cancer metabolism; cancers

DOI:  https://doi.org/10.3389/fonc.2021.644857
Front Cell Dev Biol. 2021 ;9 654337

Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer.

Rui Ma, Yinsheng Wu, Shanshan Li, Xilan Yu.

  Cancer cells reprogram glucose metabolism to meet their malignant proliferation needs and survival under a variety of stress conditions. The prominent metabolic reprogram is aerobic glycolysis, which can help cells accumulate precursors for biosynthesis of macromolecules. In addition to glycolysis, recent studies show that gluconeogenesis and TCA cycle play important roles in tumorigenesis. Here, we provide a comprehensive review about the role of glycolysis, gluconeogenesis, and TCA cycle in tumorigenesis with an emphasis on revealing the novel functions of the relevant enzymes and metabolites. These functions include regulation of cell metabolism, gene expression, cell apoptosis and autophagy. We also summarize the effect of glucose metabolism on chromatin modifications and how this relationship leads to cancer development. Understanding the link between cancer cell metabolism and chromatin modifications will help develop more effective cancer treatments.

Keywords:  epigenetic modifications; gene transcription; histone modifications; metabolism; tumorigenesis

DOI:  https://doi.org/10.3389/fcell.2021.654337
Adv Exp Med Biol. 2021 ;1269 169-177

The Warburg Effect: Historical Dogma Versus Current Rationale.

Peter Vaupel, Gabriele Multhoff.

  Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary and permanent consequence of dysfunctional mitochondria compensating for a poor ATP yield per mole glucose. Instead, the Warburg effect is an essential part of a "selfish" metabolic reprogramming, which results from the interplay between (normoxic or hypoxic) HIF-1 overexpression, oncogene activation (cMyc, Ras), loss of function of tumor suppressors (mutant p53, mutant PTEN, microRNAs and sirtuins with suppressor functions), activated (PI3K/Akt/mTORC1, Ras/Raf/Mek/Erk/c-Myc) or deactivated (AMPK) signaling pathways, components of the tumor microenvironment, and HIF-1 cooperations with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include (a) considerably accelerated glycolytic fluxes; (b) adequate ATP generation per unit time to maintain energy homeostasis; (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, nonessential amino acids, lipids, and hexosamines; (d) inhibition of pyruvate entry into mitochondria; (e) excessive formation and accumulation of lactate which stimulates tumor growth and suppression of antitumor immunity (in addition, lactate can serve as an energy source for normoxic cancer cells, contributes to extracellular acidosis, and thus drives malignant progression and resistances to conventional therapies); (f) maintenance of the cellular redox homeostasis and low ROS formation; and (g) HIF-1 overexpression, mutant p53, and mutant PTEN which inhibit mitochondrial biogenesis and functions, thus negatively impacting cellular respiration rate. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival. All in all, the Warburg effect, i.e., aerobic glycolysis in the presence of oxygen and - in principle - functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and - finally - poor patient outcome.

Keywords:  ATP generation; Aerobic glycolysis; Biosynthesis of macromolecules; Energy homeostasis; Glycolytic phenotype; Glycolytic switch; Lactate accumulation; Metabolic reprogramming; Oncogenesis; Redox homeostasis; Tumor acidosis; Tumor glucose metabolism; Tumor mitochondria; Warburg effect

DOI:  https://doi.org/10.1007/978-3-030-48238-1_27
Nat Commun. 2021 May 12. 12(1): 2748

Molecular basis for the allosteric activation mechanism of the heterodimeric imidazole glycerol phosphate synthase complex.

Jan Philip Wurm, Sihyun Sung, Andrea Christa Kneuttinger, Enrico Hupfeld, Reinhard Sterner, Matthias Wilmanns, Remco Sprangers.

Imidazole glycerol phosphate synthase (HisFH) is a heterodimeric bienzyme complex operating at a central branch point of metabolism. HisFH is responsible for the HisH-catalyzed hydrolysis of glutamine to glutamate and ammonia, which is then used for a cyclase reaction by HisF. The HisFH complex is allosterically regulated but the underlying mechanism is not well understood. Here, we elucidate the molecular basis of the long range, allosteric activation of HisFH. We establish that the catalytically active HisFH conformation is only formed when the substrates of both HisH and HisF are bound. We show that in this conformation an oxyanion hole in the HisH active site is established, which rationalizes the observed 4500-fold allosteric activation compared to the inactive conformation. In solution, the inactive and active conformations are in a dynamic equilibrium and the HisFH turnover rates correlate with the population of the active conformation, which is in accordance with the ensemble model of allostery.

DOI: https://doi.org/10.1038/s41467-021-22968-6
Cell Rep. 2021 May 11. pii: S2211-1247(21)00435-6. [Epub ahead of print]35(6): 109101

Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation.

Nicholas T Crump, Andreas V Hadjinicolaou, Meng Xia, John Walsby-Tickle, Uzi Gileadi, Ji-Li Chen, Mashiko Setshedi, Lars R Olsen, I-Jun Lau, Laura Godfrey, Lynn Quek, Zhanru Yu, Erica Ballabio, Mike B Barnkob, Giorgio Napolitani, Mariolina Salio, Hashem Koohy, Benedikt M Kessler, Stephen Taylor, Paresh Vyas, James S O McCullagh, Thomas A Milne, Vincenzo Cerundolo.

  Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase, but it is unclear how these cancers, but not T cells, tolerate arginine depletion. In this study, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPβ binding to an enhancer within ASS1. T cells cannot induce ASS1, despite the presence of active ATF4 and CEBPβ, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation, which disrupts ATF4/CEBPβ binding and target gene transcription. We find that T cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion.

Keywords:  ASS1; ATF4; H3K27me3; T cell chromatin; arginine; cancer metabolism; immunometabolism; immunosuppression; metabolic regulation; nutritional stress

DOI:  https://doi.org/10.1016/j.celrep.2021.109101
Mol Metab. 2021 Apr 30. pii: S2212-8778(21)00088-0. [Epub ahead of print] 101243

Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism.

Pengfei Liu, Matthew Dodson, Hui Li, Cody J Schmidlin, Aryatara Shakya, Yongyi Wei, Joe G N Garcia, Eli Chapman, Pawel R Kiela, Qing-Yu Zhang, Eileen White, Xinxin Ding, Aikseng Ooi, Donna D Zhang.

  NRF2, a transcription factor that regulates cellular redox and metabolic homeostasis, plays a dual role in human disease. It is well known that canonical intermittent NRF2 activation protects against diabetes-induced tissue damage. However, we show herein that in contrast to canonical NRF2 activation, prolonged non-canonical NRF2 activation via p62-mediated sequestration of KEAP1 increases carbohydrate flux through the polyol pathway, resulting in a pro-diabetic shift in glucose homeostasis. Using a combination of wild-type, Nrf2-/-, p62-/-, and Nrf2-/-;p62-/- mice and an arsenic-induced diabetes model, we demonstrate that NRF2 and p62 are essential for promoting insulin resistance and glucose intolerance. Integrated transcriptomic and metabolomic analyses reveal a p62-and NRF2-dependent increase in liver fructose metabolism and gluconeogenesis through the upregulation of four novel NRF2 target genes. In conclusion, our findings reveal a key pro-diabetic role for non-canonical NRF2 activation.

Keywords:  Diabetes; Liver carbohydrate metabolism; NRF2; Polyol pathway

DOI:  https://doi.org/10.1016/j.molmet.2021.101243
Autophagy. 2021 May 14. 1-2

Autophagy is critical for cysteine metabolism in pancreatic cancer through regulation of SLC7A11.

Subhadip Mukhopadhyay, Alec C Kimmelman.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. The elevated macroautophagy/autophagy in these tumors supports growth, promotes immune evasion, and increases therapeutic resistance. Therefore, targeting autophagy is a therapeutic strategy that is being pursued to treat PDAC patients. Whereas autophagy inhibition impairs mitochondrial metabolism in PDAC, the specific metabolite(s) that becomes limiting when autophagy is inhibited has not been identified. We report that loss of autophagy specifically results in intracellular cysteine depletion under nutrient-replete conditions. Mechanistically, we show that PDAC cells utilize the autophagy machinery to regulate the activity and localization of the cystine transporter SLC7A11 at the plasma membrane. Upon inhibition of autophagy, SLC7A11 is localized to lysosomes in an MTORC2-dependent manner. Our findings reveal a novel connection between autophagy and cysteine metabolism in pancreatic cancer.

Keywords:  Autophagy; SLC7A11; cysteine; lysosome; metabolism; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1080/15548627.2021.1922984
Biochim Biophys Acta Rev Cancer. 2021 May 06. pii: S0304-419X(21)00056-1. [Epub ahead of print]1876(1): 188559

Metabolic reprogramming in renal cancer: Events of a metabolic disease.

Samik Chakraborty, Murugabaskar Balan, Akash Sabarwal, Toni K Choueiri, Soumitro Pal.

  Recent studies have established that tumors can reprogram the pathways involved in nutrient uptake and metabolism to withstand the altered biosynthetic, bioenergetics and redox requirements of cancer cells. This phenomenon is called metabolic reprogramming, which is promoted by the loss of tumor suppressor genes and activation of oncogenes. Because of alterations and perturbations in multiple metabolic pathways, renal cell carcinoma (RCC) is sometimes termed as a "metabolic disease". The majority of metabolic reprogramming in renal cancer is caused by the inactivation of von Hippel-Lindau (VHL) gene and activation of the Ras-PI3K-AKT-mTOR pathway. Hypoxia-inducible factor (HIF) and Myc are other important players in the metabolic reprogramming of RCC. All types of RCCs are associated with reprogramming of glucose and fatty acid metabolism and the tricarboxylic acid (TCA) cycle. Metabolism of glutamine, tryptophan and arginine is also reprogrammed in renal cancer to favor tumor growth and oncogenesis. Together, understanding these modifications or reprogramming of the metabolic pathways in detail offer ample opportunities for the development of new therapeutic targets and strategies, discovery of biomarkers and identification of effective tumor detection methods.

Keywords:  Cancer; Metabolic reprogramming; Metabolism; Renal cell carcinoma

DOI:  https://doi.org/10.1016/j.bbcan.2021.188559
EMBO J. 2021 May 14. e106412

ArfGAP1 inhibits mTORC1 lysosomal localization and activation.

Delong Meng, Qianmei Yang, Chase H Melick, Brenden C Park, Ting-Sung Hsieh, Adna Curukovic, Mi-Hyeon Jeong, Junmei Zhang, Nicholas G James, Jenna L Jewell.

  The mammalian target of rapamycin complex 1 (mTORC1) integrates nutrients, growth factors, stress, and energy status to regulate cell growth and metabolism. Amino acids promote mTORC1 lysosomal localization and subsequent activation. However, the subcellular location or interacting proteins of mTORC1 under amino acid-deficient conditions is not completely understood. Here, we identify ADP-ribosylation factor GTPase-activating protein 1 (ArfGAP1) as a crucial regulator of mTORC1. ArfGAP1 interacts with mTORC1 in the absence of amino acids and inhibits mTORC1 lysosomal localization and activation. Mechanistically, the membrane curvature-sensing amphipathic lipid packing sensor (ALPS) motifs that bind to vesicle membranes are crucial for ArfGAP1 to interact with and regulate mTORC1 activity. Importantly, ArfGAP1 represses cell growth through mTORC1 and is an independent prognostic factor for the overall survival of pancreatic cancer patients. Our study identifies ArfGAP1 as a critical regulator of mTORC1 that functions by preventing the lysosomal transport and activation of mTORC1, with potential for cancer therapeutics.

Keywords:  ArfGAP1; amino acids; lysosome; mTORC1; vesicle trafficking

DOI:  https://doi.org/10.15252/embj.2020106412
ACS Nano. 2021 May 11.

Glutathione-Depleting Nanomedicines for Synergistic Cancer Therapy.

Xiaotong Cheng, Hai-Dong Xu, Huan-Huan Ran, Gaolin Liang, Fu-Gen Wu.

  Cancer cells frequently exhibit resistance to various molecular and nanoscale drugs, which inevitably affects the drugs' therapeutic outcomes. Overexpression of glutathione (GSH) has been observed in many cancer cells, and solid evidence has corroborated the resulting tumor resistance to a variety of anticancer therapies, suggesting that this biochemical characteristic of cancer cells can be developed as a potential target for cancer treatments. The single treatment of GSH-depleting agents can potentiate the responses of the cancer cells to different cell death stimuli; therefore, as an adjunctive strategy, GSH depletion is usually combined with mainstream cancer therapies for enhancing the therapeutic outcomes. Propelled by the rapid development of nanotechnology, GSH-depleting agents can be readily constructed into anticancer nanomedicines, which have shown a steep rise over the past decade. Here, we review the common GSH-depleting nanomedicines which have been widely applied in synergistic cancer treatments in recent years. Some current challenges and future perspectives for GSH depletion-based cancer therapies are also presented. With the understanding of the structure-property relationship and action mechanisms of these biomaterials, we hope that the GSH-depleting nanotechnology will be further developed to realize more effective disease treatments and even achieve successful clinical translations.

Keywords:  drug resistance; glutathione; glutathione-depleting agents; multimodal therapy; nanodrug; reactive oxygen species; redox modulation; tumor microenvironment

DOI:  https://doi.org/10.1021/acsnano.1c00498
CA Cancer J Clin. 2021 May 13.

Metabolomics in cancer research and emerging applications in clinical oncology.

Daniel R Schmidt, Rutulkumar Patel, David G Kirsch, Caroline A Lewis, Matthew G Vander Heiden, Jason W Locasale.

  Cancer has myriad effects on metabolism that include both rewiring of intracellular metabolism to enable cancer cells to proliferate inappropriately and adapt to the tumor microenvironment, and changes in normal tissue metabolism. With the recognition that fluorodeoxyglucose-positron emission tomography imaging is an important tool for the management of many cancers, other metabolites in biological samples have been in the spotlight for cancer diagnosis, monitoring, and therapy. Metabolomics is the global analysis of small molecule metabolites that like other -omics technologies can provide critical information about the cancer state that are otherwise not apparent. Here, the authors review how cancer and cancer therapies interact with metabolism at the cellular and systemic levels. An overview of metabolomics is provided with a focus on currently available technologies and how they have been applied in the clinical and translational research setting. The authors also discuss how metabolomics could be further leveraged in the future to improve the management of patients with cancer.

Keywords:  cancer; intracellular; metabolism; metabolomics

DOI:  https://doi.org/10.3322/caac.21670