Metabolomic analyzis of cells with PI3K-Akt pathway and Ras oncogene co-activation

• Grant number: 13/04142-4
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: October 05, 2013
• End date: June 04, 2014
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Sandra Martha Gomes Dias
• Grantee: Marília Meira Dias
• Supervisor: Teresa Whei-Mei Fan
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Institution abroad: University of Louisville (UofL), United States
• Associated to the scholarship: 12/11577-4 - Studies of the metabolic alterations related to the PI3K-Akt pathway and RAS oncogene co-activation., BP.PD

Abstract

Cancer is a major public health problem in many parts of the world, and is the leading cause of death in developed countries and the second leading cause of death in developing countries. Understanding the mechanisms related to tumor development and progression is essential for the improvement of therapeutic approaches to cancer and mobilizes scientific community worldwide. Different human cancers frequently arise due to genetic and epigenetic alterations in the same relatively small number of cancer pathways. Although the same pathways are commonly deregulated in different tumor types, the specific gene that is altered often varies between tumors. In most cases, mutations in different proteins of the same pathway are mutually exclusive, presumably because there is no selective advantage for a tumor cell to alter both genes, since they act in the same linear signaling pathway. An important effector of Ras is the lipid kinase PI3K and its downstream effector, protein kinase Akt. PI3K/Akt pathway is negatively regulated by the lipid phosphatase PTEN, which itself is frequently mutated in human cancers. Surprisingly, mutations in both Ras and the PTEN/PI3K/Akt signaling axis can be found in the same tumors and it was recently shown that PI3K/Akt cooperates with activation of Ras in tumorigenesis suppressing Ras-induced senescence. The increase of the glycolytic pathway even in the presence of oxygen (Warburg effect) was recently recognized as a hallmark of cancer cell transformation. The consequence of this activation is an increased glutaminolysis, which is also important for cell transformation. Glycolysis and glutaminolysis are both essential for the constant demand of the cells for lipids, proteins and nucleic acids. Since the PI3K/Akt is an effector of Ras, the present work intends to analyze the selective advantage conferred by inhibition of PTEN and activating mutation of H-RAS and K-RAS G12V and the combination of both genotypes in the glycolytic and glutaminolytic metabolism of Bj5ta and IMR90 cell lines. We also set out to understand the specific metabolic effects of mTORC2 in theses pathways through the increased expression of Rictor, and give support for the development of efficient therapeutic approaches to treat cancer. (AU)