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Importance of the low molecular weight protein tyrosine phosphatase in the tumoral metabolism reprogramming

Grant number: 17/16625-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2018
Effective date (End): May 31, 2020
Field of knowledge:Biological Sciences - Biochemistry - Enzymology
Principal Investigator:Carmen Veríssima Ferreira
Grantee:Erica Mie Akagi da Silva
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Tumor cells must assemble cellular components necessary for the synthesis of macromolecules (nucleotides, proteins, lipids) and much energy to double their genome and enlarge their biomass. To that end, tumors alter cellular metabolism to contribute to tumorigenesis and malignancy. The metabolic characteristics and pathways through which tumor cells acquire and replenish their metabolic needs is different from normal cells, due to metabolic reprogramming, a typical feature of the tumor. There is no consensus on how and what metabolic pathways are related to carcinogenesis, but many studies support the Warburg hypothesis, in which the cell uses the glycolytic pathway, metabolizing glucose to lactate even in the presence of oxygen. Other closely observed metabolic changes in tumors are: the prevalence of mitochondrial mutations, the activation of lipidic anabolic metabolism, and rapid and partial oxidation of glutamine. These metabolic reprogramming may be responsible for giving tumors malignancies. A better understanding of the metabolism of cancer cells can better elucidate the tumor itself and open doors for the design of antitumor drugs that are more effective and less toxic to normal cells. In addition, emphasis has been given on the identification of key proteins that contribute to the plasticity of tumor metabolism. Recently, our group demonstrated that low molecular weight protein tyrosine phosphatase (LMWPTP) acts as a mediator of the reprogramming of glucose metabolism in resistant leukemic cells. In the present project we will evaluate if LMWPTP plays the same role in cells of solid tumors (melanoma, pancreas and rectal colon) and if the three-dimensional (3D) culture of these cells can also influence the glycolytic profile. In addition, we intend to investigate in more detail how the LMWPTP modulates mitochondrial function. For this, hematopoietic and solid tumors lines with high and low expression of LMWPTP will be used and we will evaluate mitochondrial function (through oxygen consumption), mitochondrial protein expression (VDAC, SDH, PPARGC1A), fission modulating proteins In addition, we examined the level of expression of key lipid metabolism proteins (ACLY, FASN) and glutamine (GLUL, GLS). In this way, the present project will contribute to add new knowledge about the function of LMWPTP in the regulation of tumor cell metabolism and, therefore, to reinforce the hypothesis of this phosphatase being a therapeutic target, aiming to decrease the aggressiveness of tumor cells. (AU)