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LMW-PTP modulates glucose metabolism in cancer cells General subjects

Author:
Lori, Giulia, Gamberi, Tania, Paoli, Paolo, Caselli, Anna, Pranzini, Erica, Marzocchini, Riccardo, Modesti, Alessandra, Raugei, Giovanni
Source:
Biochimica et biophysica acta 2018 v.1862 no.12 pp. 2533-2544
ISSN:
0304-4165
Subject:
Western blotting, aerobiosis, antibodies, cell lines, glucose, glyceraldehyde-3-phosphate dehydrogenase, glycolysis, humans, insulin receptors, lactic acid, melanoma, mitochondria, molecular weight, neoplasm cells, noninsulin-dependent diabetes mellitus, oxygen consumption, phosphopyruvate hydratase, protein phosphorylation, proteomics, pyruvate kinase, triose-phosphate isomerase, two-dimensional gel electrophoresis
Abstract:
Low Molecular Weight Phosphotyrosine Protein Phosphatase (LMW-PTP) is an enzyme involved not only in tumor onset and progression but also in type 2 diabetes. A recent review shows that LMW-PTP acts on several RTK (receptor tyrosine kinase) such as PDGFR, EGFR, EphA2, Insulin receptor. It is well described also its interaction with cSrc. It is noteworthy that most of these conclusions are based on the use of cell lines expressing low levels of LMW-PTP. The aim of the present study was to discover new LMW-PTP substrates in aggressive human tumors where the over-expression of this phosphatase is a common feature.We investigated, by proteomic analysis, the protein phosphorylation pattern of A375 human melanoma cells silenced for LMW-PTP. Two-dimensional electrophoresis (2-DE) analysis, followed by western blot was performed using anti-phosphotyrosine antibodies, in order to identify differentially phosphorylated proteins.Proteomic analysis pointed out that most of the identified proteins belong to the glycolytic metabolism, such as α-enolase, pyruvate kinase, glyceraldehyde-3-phosphate dehydrogenase and triosephosphate isomerase, suggesting an involvement of LMW-PTP in glucose metabolism. Assessment of lactate production and oxygen consumption demonstrated that LMW-PTP silencing enhances glycolytic flux and slow down the oxidative metabolism. In particular, LMW-PTP expression affects PKM2 tyrosine-phosphorylation and nuclear localization, modulating its activity.All these findings propose that tumor cells are subjected to metabolic reprogramming after LMW-PTP silencing, enhancing glycolytic flux, probably to compensate the inhibition of mitochondrial metabolism.Our results highlight the involvement of LMW-PTP in regulating glucose metabolism in A375 melanoma cells.
Agid:
6107974