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Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation
- Source :
- Scientific Reports, Scientific Reports, Vol 10, Iss 1, Pp 1-17 (2020)
- Publication Year :
- 2020
- Publisher :
- Springer Nature, 2020.
-
Abstract
- 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 full-length 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.
- Subjects :
- Proteomics
Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings]
Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Differentiation [Medical Subject Headings]
Cell cycle checkpoint
Carcinogenesis
Ciclo celular
lcsh:Medicine
medicine.disease_cause
Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings]
Neoplasms
Chlorocebus aethiops
Organisms::Eukaryota::Animals [Medical Subject Headings]
lcsh:Science
Mitocondrias
Cancer
Multidisciplinary
Glutaminase
Chemistry
Cell Differentiation
Hep G2 Cells
Diseases::Neoplasms::Neoplastic Processes::Carcinogenesis [Medical Subject Headings]
Diseases::Neoplasms [Medical Subject Headings]
Cancer metabolism
Cell biology
Mitochondria
Translocación genética
COS Cells
Anatomy::Cells::Cells, Cultured::Tumor Cells, Cultured::Cell Line, Tumor::Hep G2 Cells [Medical Subject Headings]
Proliferación celular
Translocation
Cell cycle
Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Cycle::Cell Cycle Checkpoints [Medical Subject Headings]
Article
Downregulation and upregulation
Cell Line, Tumor
medicine
Glutaminasa
Animals
Humans
Author Correction
Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell Proliferation [Medical Subject Headings]
Cell Proliferation
Nucleoplasm
Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Transformed::COS Cells [Medical Subject Headings]
Oncogene
Cell growth
lcsh:R
Cell Cycle Checkpoints
Cancer cell
lcsh:Q
Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Amidohydrolases::Glutaminase [Medical Subject Headings]
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Scientific Reports, Scientific Reports, Vol 10, Iss 1, Pp 1-17 (2020)
- Accession number :
- edsair.doi.dedup.....22ffb163cafa20a6e4f277dae2bf7788