Two Faces of Glutaminase GLS2 in Carcinogenesis

Abstract

In rapidly proliferating cancer cells, glutamine is a major source of energy and building blocks. Increased glutamine uptake and enhanced glutaminolysis are key metabolic features of many cancers. Glutamine is metabolized by glutaminase (GA), which is encoded by two genes: GLS and GLS2. In contrast to isoforms arising from the GLS gene, which clearly act as oncoproteins, the role of GLS2 products in tumorigenesis is far from well understood. While in some cancer types GLS2 is overexpressed and drives cancer development, in some other types it is downregulated and behaves as a tumor suppressor gene. In this review, we describe the essential functions and regulatory mechanisms of human GLS2 and the cellular compartments in which GLS2 has been localized. Furthermore, we present the context-dependent oncogenic and tumor-suppressor properties of GLS2, and delve into the mechanisms underlying these phenomena.

Co-Expression Network Analysis Unveiled lncRNA-mRNA Links Correlated to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance and/or Intermediate Epithelial-to-Mesenchymal Transition Phenotypes in a Human Non-Small Cell Lung Cancer Cellular Model System

“…GLS2 protein promotes mitochondrial respiration and increases ATP generation in cells by catalyzing the synthesis of glutamate and alpha-ketoglutarate. The GSL2 oncogene or tumor suppressor gene in different cancer types has also been correlated with EMT [84,85].…”

GLS and GLS2 Glutaminase Isoenzymes in the Antioxidant System of Cancer Cells

“…GLS2 has been related to both tumor suppression properties and prooncogenic effects. Thus, its role in cancer is considered to be context-dependent and has been thoroughly reviewed recently [ 42 ]. However, its function as an oncogenic factor or a tumor suppressor has been related, at least partially, to its ability to modulate antioxidant capacity [ 1 ].…”

“…As reported above, the GLS and GLS2 isoenzymes are metabolic enzymes [ 42 , 43 , 54 , 63 ] whose roles may imply key antioxidant functions [ 64 , 65 , 91 , 95 ], which might lead to therapeutic implications for cancer therapy [ 15 , 16 , 26 , 35 ]. Of interest, several GLS inhibitors can block cancer progression by promoting oxidative stress [ 106 ].…”

“…PDAC 15 patients with a tumor disease at stage T3N1M0 [22] Following GLS inhibition by BPTES or CB-839, cancer cells showed decreased survival and more apoptosis associated with a lowered GSH/GSSG ratio, increased NRF2 Activation of SAT1 23 increased GLS activity and GSH synthesis, ameliorating oxidative stress to support lung cancer cell proliferation, which was blocked by inhibition of GLS, resulting in ROS accumulation NSCLC 19 A549, PC9, H1650, H1792, H358, H1944 PC9 cells were subcutaneously injected into BALB/c nude mice [33] GAC isoform was highly expressed versus KGA isoform in GBM 24 and more malignant astrocytomas Brain U87MG Astrocytomas of different malignancies [34] 1 NRF2, nuclear factor erythroid 2-like 2; 2 EMT, epithelial-to-mesenchymal transition; 3 GLS2 has been related to both tumor suppression properties and prooncogenic effects. Thus, its role in cancer is considered to be context-dependent and has been thoroughly reviewed recently [42]. However, its function as an oncogenic factor or a tumor suppressor has been related, at least partially, to its ability to modulate antioxidant capacity [1].…”

Inhibition of glutaminolysis alone and in combination with HDAC inhibitor has anti-myeloma therapeutic effects

“…Immunoblotting was performed according to previously established procedures [18,19] . U266 cells were treated with various concentrations of panobinostat and/or CB-839 for 24 h. The shRNA-transfected U266 cells were collected and lysed using a radioimmunoprecipitation assay buffer.…”