bims-glucam 2022-03-06 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022‒03‒06
eleven papers selected by
Sreeparna Banerjee
Middle East Technical University

Distinct roles of glutamine metabolism in benign and malignant cartilage tumors with IDH mutations.
Targeting ASCT2-mediated Glutamine Metabolism Inhibits Proliferation and Promotes Apoptosis of Pancreatic Cancer cell.
Decrease of Intracellular Glutamine by STF-62247 Results in the Accumulation of Lipid Droplets in von Hippel-Lindau Deficient Cells.
Therapeutic Potential of Glutamine Pathway in Lung Cancer.
CTP sensing and Mec1ATR-Rad53CHK1/CHK2 mediate a two-layered response to inhibition of glutamine metabolism.
Alcohol-driven metabolic reprogramming promotes development of RORγt-deficient thymic lymphoma.
Are we still on the right Path(way)?: the altered expression of the pentose phosphate pathway in solid tumors and the potential of its inhibition in combination therapy.
Exploring the Metabolic Landscape of AML: From Haematopoietic Stem Cells to Myeloblasts and Leukaemic Stem Cells.
Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate.
Metabolic programs tailor T cell immunity in viral infection, cancer, and aging.
Ferroptosis: An emerging therapeutic opportunity for cancer.

J Bone Miner Res. 2022 Feb 27.

Distinct roles of glutamine metabolism in benign and malignant cartilage tumors with IDH mutations.

Hongyuan Zhang, Vijitha Puviindran, Puviindran Nadesan, Xiruo Ding, Leyao Shen, Yuning J Tang, Hidetoshi Tsushima, Yasuhito Yahara, Ga I Ban, Guo-Fang Zhang, Courtney M Karner, Benjamin Alman.

  Enchondromas and chondrosarcomas are common cartilage neoplasms that are either benign or malignant respectively. The majority of these tumors harbor mutations in either IDH1 or IDH2. Glutamine metabolism has been implicated as a critical regulator of tumors with IDH mutations. Using genetic and pharmacological approaches, we demonstrated that glutaminase-mediated glutamine metabolism played distinct roles in enchondromas and chondrosarcomas with IDH1 or IDH2 mutations. Glutamine affected cell differentiation and viability in these tumors differently through different downstream metabolites. During murine enchondroma-like lesion development, glutamine-derived α-ketoglutarate promoted hypertrophic chondrocyte differentiation and regulated chondrocyte proliferation. Deletion of glutaminase in chondrocytes with Idh1 mutation increased the number and size of enchondroma-like lesions. In contrast, pharmacological inhibition of glutaminase in chondrosarcoma xenografts reduced overall tumor burden partially because glutamine-derived non-essential amino acids played an important role in preventing cell apoptosis. This study demonstrates that glutamine metabolism plays different roles in tumor initiation and cancer maintenance. Supplementation of α-ketoglutarate and inhibiting GLS may provide a therapeutic approach to suppress enchondroma and chondrosarcoma tumor growth respectively.

Keywords:  CARTILAGE TUMORS; CHONDROCYTE DIFFERENTIATION; GLUTAMINE METABOLISM; GROWTH PLATE; ISOCITRATE DEHYDROGENASE

DOI:  https://doi.org/10.1002/jbmr.4532
Biosci Rep. 2022 Mar 03. pii: BSR20212171. [Epub ahead of print]

Targeting ASCT2-mediated Glutamine Metabolism Inhibits Proliferation and Promotes Apoptosis of Pancreatic Cancer cell.

Wenbin Wang, Haihua Pan, Feihua Ren, Hongxia Chen, Ping Ren.

  Some tumor cells have a high rate of glutamine uptake and exhibit glutamine addiction. Alanine serine cysteine‑preferring transporter 2 (ASCT2) is a major mediator of glutamine supply in many tumor cells, but the underlying effects and mechanisms of ASCT2 in pancreatic cancer are largely unknown. Our results show that ASCT2 expression is significantly higher in pancreatic cancer than in normal pancreatic duct cells and pancreas. Utilizing the Kaplan-Meier Plotter Database, a high expression of SLC1A5 mRNA was significantly associated with poor overall survival in patients with pancreatic cancer. ShRNA-mediated inhibition of ASCT2 function in vitro can significantly decrease glutamine consumption, α-ketoglutarate production and ATP generation and increase the reactive oxygen species level. Moreover, the antioxidant N-acetylcysteine partially attenuated the increase in the reactive oxygen species levels and reduced ATP generation. These data suggest that ASCT2 mediates glutamine metabolism and maintains redox homeostasis in pancreatic cancer. To further investigate whether ASCT2 is involved in pancreatic cancer cell growth, we blocked ASCT2 activity with the ASCT2 inhibitor L-γ-glutamyl-p-nitroanilide and silenced the expression of ASCT2 with specific shRNAs. We found that the growth of pancreatic cancer cells was significantly inhibited. Additionally, knockdown of ASCT2 induced apoptosis through the Akt/mTOR signaling pathway. Furthermore, the loss of ASCT2 in BxPC3 cell xenografts significantly inhibited tumor growth in vivo, and this effect was associated with an increase in cleaved caspase-3 expression and a decrease in Ki67 staining. Taken together, our results show that ASCT2 may be utilized as a putative therapeutic target for pancreatic cancer.

Keywords:  ASCT2; apoptosis; glutamine metabolism; pancreatic cancer

DOI:  https://doi.org/10.1042/BSR20212171
Front Oncol. 2022 ;12 841054

Decrease of Intracellular Glutamine by STF-62247 Results in the Accumulation of Lipid Droplets in von Hippel-Lindau Deficient Cells.

Mathieu Johnson, Sarah Nowlan, Gülsüm Sahin, David A Barnett, Andrew P Joy, Mohamed Touaibia, Miroslava Cuperlovic-Culf, Daina Zofija Avizonis, Sandra Turcotte.

  Kidney cancer is one of the top ten cancer diagnosed worldwide and its incidence has increased the last 20 years. Clear Cell Renal Cell Carcinoma (ccRCC) are characterized by mutations that inactivate the von Hippel-Lindau (VHL) tumor suppressor gene and evidence indicated alterations in metabolic pathways, particularly in glutamine metabolism. We previously identified a small molecule, STF-62247, which target VHL-deficient renal tumors by affecting late-stages of autophagy and lysosomal signaling. In this study, we investigated ccRCC metabolism in VHL-deficient and proficient cells exposed to the small molecule. Metabolomics profiling using 1H NMR demonstrated that STF-62247 increases levels of glucose, pyruvate, glycerol 3-phosphate while glutamate, asparagine, and glutathione significantly decreased. Diminution of glutamate and glutamine was further investigated using mass spectrometry, western blot analyses, enzymatic activities, and viability assays. We found that expression of SLC1A5 increases in VHL-deficient cells treated with STF-62247, possibly to stimulate glutamine uptake intracellularly to counteract the diminution of this amino acid. However, exogenous addition of glutamine was not able to rescue cell viability induced by the small molecule. Instead, our results showed that VHL-deficient cells utilize glutamine to produce fatty acid in response to STF-62247. Surprisingly, this occurs through oxidative phosphorylation in STF-treated cells while control cells use reductive carboxylation to sustain lipogenesis. We also demonstrated that STF-62247 stimulated expression of stearoyl-CoA desaturase (SCD1) and peripilin2 (PLIN2) to generate accumulation of lipid droplets in VHL-deficient cells. Moreover, the carnitine palmitoyltransferase 1A (CPT1A), which control the entry of fatty acid into mitochondria for β-oxidation, also increased in response to STF-62247. CPT1A overexpression in ccRCC is known to limit tumor growth. Together, our results demonstrated that STF-62247 modulates cellular metabolism of glutamine, an amino acid involved in the autophagy-lysosome process, to support lipogenesis, which could be implicated in the signaling driving to cell death.

Keywords:  CCRCC kidney cancer; cancer; fatty acid; glutamine (Gln); lipid droplet (LD); metabolomics; von Hippel – Lindau

DOI:  https://doi.org/10.3389/fonc.2022.841054
Front Oncol. 2021 ;11 835141

Therapeutic Potential of Glutamine Pathway in Lung Cancer.

Enyu Tang, Siyang Liu, Zhiming Zhang, Rixin Zhang, Dejing Huang, Tong Gao, Tianze Zhang, Guangquan Xu.

  Cancer cells tend to obtain the substances needed for their development depending on altering metabolic characteristics. Among the reorganized metabolic pathways, Glutamine pathway, reprogrammed to be involved in the physiological process including energy supply, biosynthesis and redox homeostasis, occupies an irreplaceable role in tumor cells and has become a hot topic in recent years. Lung cancer currently maintains a high morbidity and mortality rate among all types of tumors and has been a health challenge that researchers have longed to overcome. Therefore, this study aimed to clarify the essential role of glutamine pathway played in the metabolism of lung cancer and its potential therapeutic value in the interventions of lung cancer.

Keywords:  glutaminase; glutamine; glutamine transporter; lung cancer; metabolic reprogramming; target

DOI:  https://doi.org/10.3389/fonc.2021.835141
PLoS Genet. 2022 Mar 03. 18(3): e1010101

CTP sensing and Mec1ATR-Rad53CHK1/CHK2 mediate a two-layered response to inhibition of glutamine metabolism.

Arta Ajazi, Ramveer Choudhary, Laura Tronci, Angela Bachi, Christopher Bruhn.

Glutamine analogs are potent suppressors of general glutamine metabolism with anti-cancer activity. 6-diazo-5-oxo-L-norleucine (DON) is an orally available glutamine analog which has been recently improved by structural modification for cancer treatment. Here, we explored the chemogenomic landscape of DON sensitivity using budding yeast as model organism. We identify evolutionarily conserved proteins that mediate cell resistance to glutamine analogs, namely Ura8CTPS1/2, Hpt1HPRT1, Mec1ATR, Rad53CHK1/CHK2 and Rtg1. We describe a function of Ura8 as inducible CTP synthase responding to inhibition of glutamine metabolism and propose a model for its regulation by CTP levels and Nrd1-dependent transcription termination at a cryptic unstable transcript. Disruption of the inducible CTP synthase under DON exposure hyper-activates the Mec1-Rad53 DNA damage response (DDR) pathway, which prevents chromosome breakage. Simultaneous inhibition of CTP synthase and Mec1 kinase synergistically sensitizes cells to DON, whereas CTP synthase over-expression hampers DDR mutant sensitivity. Using genome-wide suppressor screening, we identify factors promoting DON-induced CTP depletion (TORC1, glutamine transporter) and DNA breakage in DDR mutants. Together, our results identify CTP regulation and the Mec1-Rad53 DDR axis as key glutamine analog response pathways, and provide a rationale for the combined targeting of glutamine and CTP metabolism in DDR-deficient cancers.

DOI: https://doi.org/10.1371/journal.pgen.1010101
Oncogene. 2022 Mar 04.

Alcohol-driven metabolic reprogramming promotes development of RORγt-deficient thymic lymphoma.

Rui Sun, Chao Lei, Liang Chen, Liqing He, Haixun Guo, Xiang Zhang, Wenke Feng, Jun Yan, Craig J McClain, Zhongbin Deng.

RORγt is a master regulator of Th17 cells. Despite evidence linking RORγt deficiency/inhibition with metastatic thymic T cell lymphomas, the role of RORγt in lymphoma metabolism is unknown. Chronic alcohol consumption plays a causal role in many human cancers. The risk of T cell lymphoma remains unclear in humans with alcohol use disorders (AUD) after chronic RORγt inhibition. Here we demonstrated that alcohol consumption accelerates RORγt deficiency-induced lymphomagenesis. Loss of RORγt signaling in the thymus promotes aerobic glycolysis and glutaminolysis and increases allocation of glutamine carbon into lipids. Importantly, alcohol consumption results in a shift from aerobic glycolysis to glutaminolysis. Both RORγt deficiency- and alcohol-induced metabolic alterations are mediated by c-Myc, as silencing of c-Myc decreases the effects of alcohol consumption and RORγt deficiency on glutaminolysis, biosynthesis, and tumor growth in vivo. The ethanol-mediated c-Myc activation coupled with increased glutaminolysis underscore the critical role of RORγt-Myc signaling and translation in lymphoma.

DOI: https://doi.org/10.1038/s41388-022-02257-2
Expert Opin Drug Metab Toxicol. 2022 Mar 03.

Are we still on the right Path(way)?: the altered expression of the pentose phosphate pathway in solid tumors and the potential of its inhibition in combination therapy.

Caroline J W Meskers, Marika Franczak, Ryszard T Smolenski, Elisa Giovannetti, Godefridus J Peters.

  INTRODUCTION: The pentose phosphate pathway (PPP) branches from glycolysis and is crucial for cell growth, since it provides necessary compounds for anabolic reactions, nucleotide synthesis and detoxification of reactive-oxygen-species (ROS). Overexpression of PPP enzymes has been reported in multiple cancer types and linked to therapy resistance, making their inhibition interesting targets for anti-cancer therapies.AREAS COVERED: This review summarizes the extent of PPP upregulation across different cancer types, and the non-metabolic functions that PPP-enzymes might contribute to cancer initiation and maintenance. The effects of PPP-inhibition and their combinations with chemotherapeutics are summarized. We searched the databases provided by the University of Amsterdam to characterize the altered expression of the PPP across different cancer types, and to identify the effects of PPP-inhibition.
EXPERT OPINION: It can be concluded that there are synergistic and additive effects of PPP-inhibition and various classes of chemotherapeutics. These effects may be attributed to the increased susceptibility to ROS. However the toxicity, low efficacy and off-target effects of PPP-inhibitors make application in clinical practice challenging. Novel inhibitors are currently being developed, which could make PPP-inhibition a potential therapeutic strategy in the future, especially in combination with conventional chemotherapeutics and the inhibition of other metabolic pathways.

Keywords:  NAD/NADH; cancer; chemotherapy; glycolysis; pentose phosphate pathway

DOI:  https://doi.org/10.1080/17425255.2022.2049234
Front Oncol. 2022 ;12 807266

Exploring the Metabolic Landscape of AML: From Haematopoietic Stem Cells to Myeloblasts and Leukaemic Stem Cells.

Yashar Mesbahi, Toby N Trahair, Richard B Lock, Patrick Connerty.

  Despite intensive chemotherapy regimens, up to 60% of adults with acute myeloid leukaemia (AML) will relapse and eventually succumb to their disease. Recent studies suggest that leukaemic stem cells (LSCs) drive AML relapse by residing in the bone marrow niche and adapting their metabolic profile. Metabolic adaptation and LSC plasticity are novel hallmarks of leukemogenesis that provide important biological processes required for tumour initiation, progression and therapeutic responses. These findings highlight the importance of targeting metabolic pathways in leukaemia biology which might serve as the Achilles' heel for the treatment of AML relapse. In this review, we highlight the metabolic differences between normal haematopoietic cells, bulk AML cells and LSCs. Specifically, we focus on four major metabolic pathways dysregulated in AML; (i) glycolysis; (ii) mitochondrial metabolism; (iii) amino acid metabolism; and (iv) lipid metabolism. We then outline established and emerging drug interventions that exploit metabolic dependencies of leukaemic cells in the treatment of AML. The metabolic signature of AML cells alters during different biological conditions such as chemotherapy and quiescence. Therefore, targeting the metabolic vulnerabilities of these cells might selectively eradicate them and improve the overall survival of patients with AML.

Keywords:  acute myeloid leukaemia; cancer metabolism; leukaemic stem cells; metabolic plasticity; metabolic targeting

DOI:  https://doi.org/10.3389/fonc.2022.807266
Nat Metab. 2022 Feb;4(2): 225-238

Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate.

Mengjia Zhao, Pengbo Yao, Youxiang Mao, Jinjun Wu, Weihua Wang, Chenhui Geng, Jie Cheng, Wenjing Du, Peng Jiang.

Many types of cancer feature TP53 mutations with oncogenic properties. However, whether the oncogenic activity of mutant p53 is affected by the cellular metabolic state is unknown. Here we show that cancer-associated mutant p53 protein is stabilized by 2-hydroxyglutarate generated by malic enzyme 2. Mechanistically, malic enzyme 2 promotes the production of 2-hydroxyglutarate by adjusting glutaminolysis, as well as through a reaction that requires pyruvate and NADPH. Malic enzyme 2 depletion decreases cellular 2-hydroxyglutarate levels in vitro and in vivo, whereas elevated malic enzyme 2 expression increases 2-hydroxyglutarate production. We further show that 2-hydroxyglutarate binds directly to mutant p53, which reduces Mdm2-mediated mutant p53 ubiquitination and degradation. 2-Hydroxyglutarate supplementation is sufficient for maintaining mutant p53 protein stability in malic enzyme 2-depleted cells, and restores tumour growth of malic enzyme 2-ablated cells, but not of cells that lack mutant p53. Our findings reveal the previously unrecognized versatility of malic enzyme 2 catalytic functions, and uncover a role for mutant p53 in sensing cellular 2-hydroxyglutarate levels, which contribute to the stabilization of mutant p53 and tumour growth.

DOI: https://doi.org/10.1038/s42255-022-00532-w
Cell Metab. 2022 Mar 01. pii: S1550-4131(22)00047-X. [Epub ahead of print]34(3): 378-395

Metabolic programs tailor T cell immunity in viral infection, cancer, and aging.

Sofie Hedlund Møller, Pei-Chun Hsueh, Yi-Ru Yu, Lianjun Zhang, Ping-Chih Ho.

  Productive T cell responses to infection and cancer rely on coordinated metabolic reprogramming and epigenetic remodeling among the immune cells. In particular, T cell effector and memory differentiation, exhaustion, and senescence/aging are tightly regulated by the metabolism-epigenetics axis. In this review, we summarize recent advances of how metabolic circuits combined with epigenetic changes dictate T cell fate decisions and shape their functional states. We also discuss how the metabolic-epigenetic axis orchestrates T cell exhaustion and explore how physiological factors, such as diet, gut microbiota, and the circadian clock, are integrated in shaping T cell epigenetic modifications and functionality. Furthermore, we summarize key features of the senescent/aged T cells and discuss how to ameliorate vaccination- and COVID-induced T cell dysfunctions by metabolic modulations. An in-depth understanding of the unexplored links between cellular metabolism and epigenetic modifications in various physiological or pathological contexts has the potential to uncover novel therapeutic strategies for fine-tuning T cell immunity.

Keywords:  CD8; COVID; aging; epigenetic; exhaustion; immunometabolism

DOI:  https://doi.org/10.1016/j.cmet.2022.02.003
Genes Dis. 2022 Mar;9(2): 334-346

Ferroptosis: An emerging therapeutic opportunity for cancer.

Liyuan Wang, Xiaoguang Chen, Chunhong Yan.

  Ferroptosis, a new form of non-apoptotic, regulated cell death characterized by iron dependency and lipid peroxidation, is involved in many pathological conditions such as neurodegenerative diseases, heart ischemia/reperfusion injury, acute renal failure, and cancer. While metabolic dysfunctions can lead to excessive lipid peroxidation culminating in ferroptotic cell death, glutathione peroxidase 4 (GPX4) resides in the center of a network that functions to prevent lipid hydroperoxides from accumulation, thereby suppressing ferroptosis. Indeed, RSL3 and other small-molecule GPX4 inhibitors can induce ferroptosis in not only cultured cancer cells but also tumor xenografts implanted in mice. Similarly, erastin and other system Xc- inhibitors can deplete intracellular glutathione required for GPX4 function, leading to lipid peroxidation and ferroptosis. As therapy-resistant cancer cells are sensitive to GPX4-targeted therapeutic regimens, the agents capable of inducing ferroptosis hold great promises to improve current cancer therapy. This review will outline the molecular basis of ferroptosis, but focus on the strategies and the agents developed in recent years for therapeutic induction of ferroptosis. The potentials of these ferroptosis-inducing agents, which include system Xc- inhibitors, GPX4 inhibitors, and iron-based nanoparticles, in cancer therapy will be subsequently discussed.

Keywords:  Cancer therapy; Erastin; Ferroptosis; GPX4; Lipid peroxidation; Nanomedicine; RSL3; System Xc-

DOI:  https://doi.org/10.1016/j.gendis.2020.09.005