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3-bromopyruvate as molecular tool to uncover the biological basis of protein phosphatase LMWPTP contribution to leukemic cells resistance

Grant number: 15/11433-0
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): August 01, 2015
Effective date (End): June 13, 2016
Field of knowledge:Biological Sciences - Biochemistry - Enzymology
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Carmen Veríssima Ferreira
Grantee:Emanuella Maria Barreto Fonseca
Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil


The great challenge of cancer therapy is to overcome the resistance to chemotherapy and metastasis. Therefore, a better understanding of these processes, the identification of molecular targets, and the development of new drugs with higher efficiency have been aimed of several research groups. In this scenario, our group initiated the investigation on the importance of the low molecular weight protein tyrosine phosphatase (LMWPTP) in 2005 and since then we showed that protein phosphatases inhibitors could be useful to increase the responsiveness of tumor cells to traditional chemotherapeutic. Then we established a collaboration with two groups from The Netherlands and it was possible to demonstrate that the LMWPTP contributes to: the maintenance of resistant phenotype and metastasis of solid tumors (prostate and rectal colon) and leukemia (myeloid leukemia human chronic). Besides, we observed that in samples from patients with prostate and colon cancer, the higher expression and activity of this enzyme correlate to the degree of aggressiveness, resistance and death of patients due to the tumor. Under the molecular aspect, until the moment, we demonstrate that the presence of LMWPTP ensures the activity of protein kinases related to survival and proliferation, and predominance of the glycolytic metabolism (glucose ’ lactate). Therefore, in this project we will focus on: 1) the inhibitory studies of LMWPTP by 3-bromopyruvate, an alkylating agent capable of causing great impact on the energy metabolism and consequently cell death; 2) the understanding of how this enzyme define the glucose metabolism fate in leukemia cells. Several tumor cells reprogram glucose metabolism in order to increase the synthesis of molecules that are crucial for the proliferation, resistance and adaptation to a hypoxic microenvironment. Therefore, with this project we intend to better understand how the LMWPTP contributes for leukemia resistance, to reinforce our hypothesis that this enzyme might be an interesting target and to demonstrate that part of the anti-tumor action of 3BP is due to inhibition of LMWPTP. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FARIA, ALESSANDRA V. S.; FONSECA, EMANUELLA M. B.; FERNANDES-OLIVEIRA, PATRICIA DE S.; DE LIMA, TANES I.; CLERICI, STEFANO P.; JUSTO, GISELLE Z.; SILVEIRA, LEONARDO R.; DURAN, NELSON; FERREIRA-HALDER, CARMEN, V. Violacein switches off low molecular weight tyrosine phosphatase and rewires mitochondria in colorectal cancer cells. BIOORGANIC CHEMISTRY, v. 127, p. 9-pg., . (17/08119-8, 20/04409-4, 15/20412-7, 15/11433-0, 18/03593-6)
FARIA, ALESSANDRA V. S.; FONSECA, EMANUELLA MARIA BARRETO; CORDEIRO, HELON GUIMARAES; CLERICI, STEFANO PIATTO; FERREIRA-HALDER, CARMEN VERISSIMA. Low molecular weight protein tyrosine phosphatase as signaling hub of cancer hallmarks. CELLULAR AND MOLECULAR LIFE SCIENCES, v. 78, n. 4, p. 1263-1273, . (17/08119-8, 15/11433-0, 18/03593-6)
PELIZZARO ROCHA-BRITO, KARIN JULIANE; BARRETO FONSECA, EMANUELLA MARIA; DE FREITAS OLIVEIRA, BRENO GERMANO; DE FATIMA, ANGELO; FERREIRA-HALDER, CARMEN VERISSIMA. Calix[6]arene diminishes receptor tyrosine kinase lifespan in pancreatic cancer cells and inhibits their migration and invasion efficiency. BIOORGANIC CHEMISTRY, v. 100, . (15/11433-0, 13/08896-3)

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