Pan-Cancer Metabolic Signature Predicts Co-Dependency on Glutaminase and De Novo Glutathione Synthesis Linked to a High-Mesenchymal Cell State

Daemen, Anneleen; Liu, Bonnie; Song, Kyung; Kwong, Mandy; Gao, Min; Hong, Rebecca; Nannini, Michelle; Peterson, David; Liederer, Bianca M.; Cruz, Cecile de la; Sangaraju, Dewakar; Jaochico, Allan; Zhao, Xiaofeng; Sandoval, Wendy; Hunsaker, Thomas; Firestein, Ron; Latham, Sheerin; Sampath, Deepak; Evangelista, Marie; Hatzivassiliou, Georgia

doi:10.1016/j.cmet.2018.06.003

Cited by 74 publications

(66 citation statements)

References 60 publications

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“…Notably, if GLS2 has location-specific functions independent of glutaminolysis in cell nuclei, it could become a promising target. Actually, the pattern of GLS and GLS2 expression differentially modulate the clinical outcome of cancers 55 and is becoming a useful metabolic signature to diagnose responders to GLS cancer therapy 56,57 .…”

Section: Scientific Reports |mentioning

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: Scientific Reports |mentioning

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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“…Surprisingly, our pharmacometabolic studies revealed that C968 treatment neither increased intracellular Gln, nor did it reduce the concentrations of Glu, Glu-dependent amino acids (Ala, Asp) or the TCA cycle intermediate Suc (Fig. 5), all validated metabolic indicators for successful GLS suppression 51,57,60 . This suggests that the phenotypes observed upon C968 treatment (Figs.…”

Section: Discussionmentioning

confidence: 79%

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

et al. 2020

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Cancer cells upregulate anabolic processes to maintain high rates of cellular turnover. Limiting the supply of macromolecular precursors by targeting enzymes involved in biosynthesis is a promising strategy in cancer therapy. Several tumors excessively metabolize glutamine to generate precursors for nonessential amino acids, nucleotides, and lipids, in a process called glutaminolysis. Here we show that pharmacological inhibition of glutaminase (GLS) eradicates glioblastoma stem-like cells (GSCs), a small cell subpopulation in glioblastoma (GBM) responsible for therapy resistance and tumor recurrence. Treatment with small molecule inhibitors compound 968 and CB839 effectively diminished cell growth and in vitro clonogenicity of GSC neurosphere cultures. However, our pharmaco-metabolic studies revealed that only CB839 inhibited GLS enzymatic activity thereby limiting the influx of glutamine derivates into the TCA cycle. Nevertheless, the effects of both inhibitors were highly GLS specific, since treatment sensitivity markedly correlated with GLS protein expression. Strikingly, we found GLS overexpressed in in vitro GSC models as compared with neural stem cells (NSC). Moreover, our study demonstrates the usefulness of in vitro pharmacometabolomics to score target specificity of compounds thereby refining drug development and risk assessment.

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“…3, A and C). Notably, the up-regulation of GLS was confined to the spliced isoform glutaminase C (GLS-GAC) (approximately 4.5-fold change Mfn2cKO/CTRL, P = 0.05), whose specific up-regulation is observed in cancer tissue to support mitochondrial bioenergetics (27). The fact that BCAA catabolism emerged as one of the key up-regulated pathways in our analysis strongly suggests that the anaplerotic flux into the TCA cycle may be altered in OXPHOSdeficient PNs.…”

Section: Mitochondrial Dysfunction In Neurons Induces Tca Cycle Anaplmentioning

confidence: 99%

Neuronal metabolic rewiring promotes resilience to neurodegeneration caused by mitochondrial dysfunction

et al. 2020

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Neurodegeneration in mitochondrial disorders is considered irreversible because of limited metabolic plasticity in neurons, yet the cell-autonomous implications of mitochondrial dysfunction for neuronal metabolism in vivo are poorly understood. Here, we profiled the cell-specific proteome of Purkinje neurons undergoing progressive OXPHOS deficiency caused by disrupted mitochondrial fusion dynamics. We found that mitochondrial dysfunction triggers a profound rewiring of the proteomic landscape, culminating in the sequential activation of precise metabolic programs preceding cell death. Unexpectedly, we identified a marked induction of pyruvate carboxylase (PCx) and other anaplerotic enzymes involved in replenishing tricarboxylic acid cycle intermediates. Suppression of PCx aggravated oxidative stress and neurodegeneration, showing that anaplerosis is protective in OXPHOS-deficient neurons. Restoration of mitochondrial fusion in end-stage degenerating neurons fully reversed these metabolic hallmarks, thereby preventing cell death. Our findings identify a previously unappreciated pathway conferring resilience to mitochondrial dysfunction and show that neurodegeneration can be reversed even at advanced disease stages.

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Pan-Cancer Metabolic Signature Predicts Co-Dependency on Glutaminase and De Novo Glutathione Synthesis Linked to a High-Mesenchymal Cell State

Cited by 74 publications

References 60 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

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

Neuronal metabolic rewiring promotes resilience to neurodegeneration caused by mitochondrial dysfunction

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