Structural and functional studies of key proteins underlying the metabolic adaptation process in tumors

• Grant number: 10/05003-0
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2010
• End date: June 30, 2012
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Andre Luis Berteli Ambrosio
• Grantee: Andre Luis Berteli Ambrosio
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Associated researchers: Sandra Martha Gomes Dias

Abstract

Cancer cells contain genetic alterations arising from point mutations, deletions, genetic rearrangements, and gene amplification that result in aberrant signaling activities and loss of cell growth control. With recent publications showing that previously known ontogenesis regulates metabolic pathways, understanding and targeting the source of metabolites important for proliferation has become a viable strategy in fighting neoplastic transformation. Besides aerobic glycolysis, high levels of glutaminolysis are also a hallmark exhibited in most tumors and both are required in order to maintain its proliferative capacity. Under this context, we propose structural studies of two groups of proteins that actively participate in the maintenance of such phenotype: the glutaminases and the transcription factor HIF-1. Mammals contain two distinct but structurally related genes encoding proteins collectively referred to as glutaminase, with one form being highly expressed in liver and another form being found in kidney and a number of tissues including many transformed cells. Glutaminase C is a splice-variant of the latter and is of special interest as it is currently being evaluated as a target for the development of alternative therapeutics to fight the aberrant glutaminolytic phenotype. In normal cells, HIF-1 mediates adaptive responses to changes in tissue oxygenation, regulating the transcription of more than 70 known target genes. In human cancers it is produced as a result of either intratumoral hypoxia or genetic alterations, such as gain-of-function mutations in ontogenesis and loss-of-function mutations in tumor-suppressor gene. HIF-1 activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Overall, the motivation to conduct theses studies is substantial and we anticipate that the better understanding of both the structural organization and the mechanisms of activation and inhibition of these proteins has the potential to generate high-value therapeutic options for cancer treatment in the future. (AU)

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)

CASSAGO, ALEXANDRE; FERREIRA, AMANDA P. S.; FERREIRA, IGOR M.; FORNEZARI, CAMILA; GOMES, EMERSON R. M.; GREENE, KAI SU; PEREIRA, HUMBERTO M.; GARRATT, RICHARD C.; DIAS, SANDRA M. G.; AMBROSIO, ANDRE L. B.. Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 109, n. 4, p. 1092-1097, JAN 24 2012. (10/05003-0, 09/10875-9, 10/05987-0)

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, SEP 27 2013. (12/14298-9, 10/05003-0, 09/10875-9, 10/05987-0, 09/54067-3, 11/06654-7)