Multiomics Analysis Reveals that GLS and GLS2 Differentially Modulate the Clinical Outcomes of Cancer

Saha, Subbroto Kumar; Islam, Saiful; Abdullah-Al-Wadud, M.; Ali, Farman; Park, Kyoung Sik

doi:10.3390/jcm8030355

Cited by 68 publications

(54 citation statements)

References 90 publications

(98 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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

show abstract

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

View full text Add to dashboard Cite

show abstract

“…GLS2 restoration in HCC cells negatively regulates phosphatidylinositol 3-kinase (PI3K/AKT) signaling, promoting the inhibition of migration, invasion and metastasis, and reducing the size of HCC xenograft tumors [50]. In contrast, other studies demonstrated the oncogenic activity of GLS2, where its overexpression is associated with poor overall survival in blood, colorectal, ovarian and thymoma cancers [51].…”

Section: Glutamine Metabolism In Cancermentioning

confidence: 99%

Non-Coding RNAs as Key Regulators of Glutaminolysis in Cancer

Ortiz-Pedraza

Muñoz-Bello

Olmedo-Nieva

et al. 2020

IJMS

View full text Add to dashboard Cite

Cancer cells exhibit exacerbated metabolic activity to maintain their accelerated proliferation and microenvironmental adaptation in order to survive under nutrient-deficient conditions. Tumors display an increase in glycolysis, glutaminolysis and fatty acid biosynthesis, which provide their energy source. Glutamine is critical for fundamental cellular processes, where intermediate metabolites produced through glutaminolysis are necessary for the maintenance of mitochondrial metabolism. These include antioxidants to remove reactive oxygen species, and the generation of the nonessential amino acids, purines, pyrimidines and fatty acids required for cellular replication and the activation of cell signaling. Some cancer cells are highly dependent on glutamine consumption since its catabolism provides an anaplerotic pathway to feed the Krebs cycle. Intermediate members of the glutaminolysis pathway have been found to be deregulated in several types of cancers and have been proposed as therapeutic targets and prognostic biomarkers. This review summarizes the main players in the glutaminolysis pathway, how they have been found to be deregulated in cancer and their implications for cancer maintenance. Furthermore, non-coding RNAs are now recognized as new participants in the regulation of glutaminolysis; therefore, their involvement in glutamine metabolism in cancer is discussed in detail.Int. J. Mol. Sci. 2020, 21, 2872 2 of 26 an increased glucose consumption in relation to normal differentiated tissues. Now we know that glutamine metabolism is as important as glucose metabolism for the production of macromolecules in cancer [1].Glutamine is an abundant amino acid involved in energy production, homeostasis in pro/antioxidant species and the activation of signaling pathways in cancer. In addition to the antioxidant glutathione (GSH), nucleotides, lipids and amino acids are formed from glutamine metabolism. All of these are needed for many metabolic functions such as growth, proliferation, cell survival and defense against oxidative stress [2]. Glutamine contributes, with reduced nitrogen, to the de novo biosynthesis of diverse nitrogen-containing compounds, such as purine and pyrimidine nucleotides, glucosamine-6-phosphate and nonessential amino acids.As glutamine is the most abundant amino acid in the blood and muscle tissue, normal proliferating cells use glutamine metabolism as an energy source, mediated by its catabolic products, glutamate and α-ketoglutarate (α-kG), the latter being an intermediate of the tricarboxylic acid cycle (TCA) or Krebs cycle [3]. In 1950, Harry Eagle observed that HeLa tumor cells require an excess of glutamine, in relation to other amino acids in the culture medium, for optimal growth. Furthermore, it has been reported that tumors consume glutamine faster than the surrounding normal tissue [4]. Moreover, most cancer cells are dependent on glutamine being unable to survive under glutamine starvation, an effect that has been termed glutamine addiction [5]. Various types of cancers are high...

show abstract

“…Simultaneous expression of GLS and GLS2 isoforms were also confirmed for several human cancer cells at the transcriptome and proteome levels (Turner and McGivan, 2003;Pérez-Gómez et al, 2005). In different types of cancer, such as bladder, colon and lung cancer, GLS2 is considerably overexpressed compared with normal tissues (Saha et al, 2019).…”

Section: Expressionmentioning

confidence: 99%

“…This is in agreement with the loss of GLS2 expression in hepatocellular carcinomas (Suzuki et al, 2010) and brain tumors (Szeliga et al, 2005). However, this behavior of GLS2 is not universal, as there are some types of cancer -cervical and lung cancers, NMYC-amplified neuroblastoma -where GLS2 expression is upregulated and this upregulation is associated with therapeutic resistance and poor clinical outcomes (Xiang et al, 2013;Xiang et al, 2015;Saha et al, 2019). Interacting partners: the first protein-interacting partners of GLS2 were discovered by two-hybrid genetic screening of a human brain cDNA library, using the C-terminal region of GLS2 as bait.…”

Section: Functionmentioning

confidence: 99%

See 1 more Smart Citation

GLS2 (Glutaminase 2)

Campos-Sandoval¹,

Martín-Rufián²,

Márquez³

2019

Atlas of Genetics and Cytogenetics in Oncology and Haematology

View full text Add to dashboard Cite

Mammalian glutaminases are encoded by two paralogous genes, Gls and Gls2, presumably derived by gene duplication of a common ancestor. Each gene codes for two different isoforms. The two transcripts of Gls2, named GAB and LGA, arise through a surrogate promoter usage mechanism. In certain types of malignancies, such as glioblastoma and liver cancers, expression of GLS2 gene is repressed by promoter hypermethylation, which could contribute to the malignant process. The finding that ectopic expression of GLS2 could inhibit proliferation of these tumors led to the hypothesis that this isoenzyme, a transcriptional target of TP53, might play a role as tumor suppressor, in opposition to GLS, regulated by oncogenes and associated to tumorigenesis. However, recent findings indicate that GLS2 is upregulated in some types of cancer (NMYC-amplified neuroblastoma, cervical, colon and lung cancers) and this upregulation paradoxically correlates with poor clinical outcomes.

show abstract

Multiomics Analysis Reveals that GLS and GLS2 Differentially Modulate the Clinical Outcomes of Cancer

Cited by 68 publications

References 90 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

Non-Coding RNAs as Key Regulators of Glutaminolysis in Cancer

GLS2 (Glutaminase 2)

Contact Info

Product

Resources

About