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Cancer metabolic adaptation: structural and functional studies of key proteins

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)

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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)
DIAS, MARILIA M.; ADAMOSKI, DOUGLAS; DOS REIS, LARISSA M.; ASCENCAO, CAROLLINE F. R.; DE OLIVEIRA, KRISHINA R. S.; PASCHOALINI MAFRA, ANA CAROLINA; DA SILVA BASTOS, ALLINY CRISTINY; QUINTERO, MELISSA; CASSAGO, CAROLINA DE G.; FERREIRA, IGOR M.; et al. GLS2 is protumorigenic in breast cancers. Oncogene, v. 39, n. 3, p. 690-702, . (13/05668-0, 14/18061-9, 12/14298-9, 13/23510-4, 14/17820-3, 14/06512-6, 14/15968-3, 15/25832-4, 12/09452-9, 14/20673-2, 16/06625-0, 12/11577-4, 11/10127-2)
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; et al. 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, . (12/14298-9, 10/13739-6, 14/04927-4, 14/20673-2, 14/15968-3)
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; et al. 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, . (12/14298-9, 10/05003-0, 09/10875-9, 10/05987-0, 09/54067-3, 11/06654-7)

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