Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer

Matés, José M.; Paola, Floriana J. Di; Campos-Sandoval, José A.; Mazurek, Sybille; Márquez, Javier

doi:10.1016/j.semcdb.2019.05.012

Cited by 103 publications

(88 citation statements)

References 117 publications

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“…Emerging experimental evidences support that GA isozymes exhibit multiple functions 32 . Elucidation of the respective role of each GA isoform may be of profound physiological significance not only in normal conditions, but also in pathological states like cancer where GLS and GLS2 isoenzymes seem to play apparently opposing roles 3 .…”

Section: Discussionmentioning

confidence: 99%

Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation

Oliva

Campos-Sandoval

Gómez-García

et al. 2020

Sci Rep

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Glutaminase (GA) catalyzes the first step in mitochondrial glutaminolysis playing a key role in cancer metabolic reprogramming. Humans express two types of GA isoforms: GLS and GLS2. GLS isozymes have been consistently related to cell proliferation, but the role of GLS2 in cancer remains poorly understood. GLS2 is repressed in many tumor cells and a better understanding of its function in tumorigenesis may further the development of new therapeutic approaches. We analyzed GLS2 expression in HCC, GBM and neuroblastoma cells, as well as in monkey COS-7 cells. We studied GLS2 expression after induction of differentiation with phorbol ester (PMA) and transduction with the fulllength cDNA of GLS2. In parallel, we investigated cell cycle progression and levels of p53, p21 and c-Myc proteins. Using the baculovirus system, human GLS2 protein was overexpressed, purified and analyzed for posttranslational modifications employing a proteomics LC-MS/MS platform. We have demonstrated a dual targeting of GLS2 in human cancer cells. Immunocytochemistry and subcellular fractionation gave consistent results demonstrating nuclear and mitochondrial locations, with the latter being predominant. Nuclear targeting was confirmed in cancer cells overexpressing c-Myc-and GFP-tagged GLS2 proteins. We assessed the subnuclear location finding a widespread distribution of GLS2 in the nucleoplasm without clear overlapping with specific nuclear substructures. GLS2 expression and nuclear accrual notably increased by treatment of SH-SY5Y cells with PMA and it correlated with cell cycle arrest at G2/M, upregulation of tumor suppressor p53 and p21 protein. A similar response was obtained by overexpression of GLS2 in T98G glioma cells, including downregulation of oncogene c-Myc. Furthermore, human GLS2 was identified as being hypusinated by MS analysis, a posttranslational modification which may be relevant for its nuclear targeting and/or function. Our studies provide evidence for a tumor suppressor role of GLS2 in certain types of cancer. The data imply that GLS2 can be regarded as a highly mobile and multilocalizing protein translocated to both mitochondria and nuclei. Upregulation of GLS2 in cancer cells induced an antiproliferative response with cell cycle arrest at the G2/M phase.Altered metabolism is a hallmark of cancer 1 and the term "metabolic reprogramming" has been coined to describe the whole range of metabolic abnormalities accompanying tumorigenesis and metastasis 2 . Increased

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Section: Discussionmentioning

confidence: 99%

Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation

Oliva

Campos-Sandoval

Gómez-García

et al. 2020

Sci Rep

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“…Importantly, it was demonstrated that glutamine could be useful for cancer cells to drive tumor growth due to is used for energy generation as well as for biomass accumulation being a source of carbon and nitrogen as mentioned before (152), moreover glutamine can be consumed by proliferating cells more rapidly than needed to satisfy nitrogen requirements (155). As a result of glutamine depletion, most cancer patient's loss body weight due to muscle mass consumption provoking weakness, all these symptoms are known as cachexia (155,156).…”

Section: Glutaminolysis and Mtorc1 In Cancermentioning

confidence: 85%

“…Carbon and nitrogen from the glutamine present in blood are used for biosynthesis and also for providing energy to the cell (151). Specifically, glutamine is the leading donor of nitrogen for purine and pyrimidine nucleotide synthesis, as well as a supplier for amino groups for non-essential amino acids synthesis, such as aspartate, alanine, glycine and serine, moreover, nitrogen from glutamine participates in nucleic acid and de novo protein synthesis (149,152). Finally, the glutamine-derived carbon is source for fatty acid and amino acid synthesis as well (151).…”

Section: Glutaminolysis and Mtorc1 In Cancermentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients. de la Cruz López et al. mTORC1 and Mitochondrial Functions Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation, though no other collaboration, with with several of the authors AG and KC.

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“…Pyruvate in cancer cells is converted to lactic acid mainly through glycolysis reaction, and a very small amount of it enters the mitochondria for TCA cycle, while cancer cells can continue the mitochondrial TCA cycle by consuming glutamine. [ ] Therefore, glycolysis and glutamine consumption are the key links in energy supply of cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Kruppel-like factor 2 disturb non-small cell lung cancer energy metabolism by inhibited glutamine consumption

Song

Jin‐Xiang

Tian

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Metabolic reprogramming is well accepted as a hallmark of cancer. This study aimed to explore the role of Kruppel-like factor 2 (KLF2) in aerobic glycolysis and glutamine consumption of energy metabolism in non-small cell lung cancer (NSCLC) cells. Methods Two different NSCLC cells, A549 and NCI-H1299, were used to investigate the role of KLF2 in glycolysis and glutamine consumption by tracer technique and KLF2 transfection. Key findings The results showed that overexpression KLF could inhibit the energy metabolism and proliferation of NSCLC cells, but had no significant effect on glycolysis reaction and only affected the glutamine consumption of NSCLC cells. In NSCLC cells exposed to glutamine deprivation, the effect of overexpression of KLF2 on cell proliferation and energy metabolism disappeared. It was found that KLF2 could inhibit the expression of glutaminase (GLS) by metabolite tracing technique and so on. However, when GLS inhibitors were given to overexpressing KLF2 NSCLC cells, the intervention effect of KLF2 disappeared. Conclusions Kruppel-like factor 2 could decrease the level of glutamine, participate in the consumption of glutamine by cancer cells, and then inhibit the energy metabolism of cancer cells.

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Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer

Cited by 103 publications

References 117 publications

Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation

Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

Kruppel-like factor 2 disturb non-small cell lung cancer energy metabolism by inhibited glutamine consumption

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