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Cancer metabolic adaptation: structural and functional studies of key proteins

Grant number: 12/14298-9
Support type:Regular Research Grants
Duration: October 01, 2012 - September 30, 2014
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Andre Luis Berteli Ambrosio
Grantee:Andre Luis Berteli Ambrosio
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil
Assoc. researchers:Juliana Ferreira de Oliveira ; Sandra Martha Gomes Dias

Abstract

In order to sustain an inherently proliferative phenotype, cancer cells are in constant process of adaptation to the types and levels of available nutrients in the cellular microenvironment they inhabit. It is now known that the ability to metabolically adapt is primarily associated with activation of oncogenes or loss of tumor suppressors, which in turn result in selection by overexpression or isoforms of proteins that once were tightly regulated in normal cells. For instance, in contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, even under normoxia, a phenomenon termed " Warburg effect". The amino acid glutamine and sugar glucose are two of the most important and versatile nutrients in this context. Both serve as the main sources of carbon skeletons (for nucleotide synthesis, amino acids and lipids), generattion energy in the form of ATP and recycling of reducing agents, such as NADPH, all essential to the process of growth, biomass doubling and subsequent cell division. In this context, this research project aims to examine, from the structural, biochemical and biophysical standpoints, four key components to maintaining high demands of biosynthetic and bioenergetic characteristics of cancer cells: (1) the phosphate-dependent glutaminases, which are key enzymes in the process of TCA cycle anaplerosis and thereby maintaining mitochondrial homeostasis; the (2) HIF-1 and (3) MondoA transcription factors, which directly govern the expression of hundreds of genes involved in glucose metabolism, directly responding to the intracellular levels of this nutrient; and the (4) mitochondrial pyruvate carrier, or MPC, which is a transmembrane complex that performs the transport of cytosolic pyruvate to mitocodria. (AU)

Articles published in Agência FAPESP Newsletter about the research grant
Researchers discover previously unknown link between protein and fatty acids 

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)
FALA, ANGELA M.; OLIVEIRA, JULIANA F.; ADAMOSKI, DOUGLAS; ARICETTI, JULIANA A.; DIAS, MARILIA M.; DIAS, MARCIO V. B.; SFORCA, MAURCIO L.; LOPES-DE-OLIVEIRA, PAULO S.; ROCCO, SILVANA A.; CALDANA, CAMILA; DIAS, SANDRA M. G.; AMBROSIO, ANDRE L. B. Unsaturated fatty acids as high-affinity ligands of the C-terminal Per-ARNT-Sim domain from the Hypoxia-inducible factor 3 alpha. SCIENTIFIC REPORTS, v. 5, AUG 3 2015. Web of Science Citations: 8.
SCOTA FERREIRA, AMANDA PETRINA; CASSAGO, ALEXANDRE; GONCALVES, KALIANDRA DE ALMEIDA; DIAS, MARILIA MEIRA; ADAMOSKI, DOUGLAS; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; HONORATO, RODRIGO VARGAS; DE OLIVEIRA, JULIANA FERREIRA; FERREIRA, IGOR MONTEZE; FORNEZARI, CAMILA; BETTINI, JEFFERSON; LOPES OLIVEIRA, PAULO SERGIO; PAES LEME, ADRIANA FRANCO; PORTUGAL, RODRIGO VILLARES; BERTELI AMBROSIO, ANDRE LUIS; GOMES DIAS, SANDRA MARTHA. Active Glutaminase C Self-assembles into a Supratetrameric Oligomer That Can Be Disrupted by an Allosteric Inhibitor. Journal of Biological Chemistry, v. 288, n. 39, p. 28009-28020, SEP 27 2013. Web of Science Citations: 30.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.