Studies of the metabolic alterations related to the PI3K-Akt pathway and RAS oncogene co-activation.

• Grant number: 12/11577-4
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): August 01, 2012
• Effective date (End): August 01, 2016
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal researcher: Sandra Martha Gomes Dias
• Grantee: Marília Meira Dias
• Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovações (Brasil). Campinas , SP, Brazil
• Associated research grant: 09/10875-9 - Cellular and biochemical studies of the glutaminase enzyme and its relation with cancer, AP.JP
• Associated scholarship(s): 13/04142-4 - Metabolomic analyzis of cells with PI3K-Akt pathway and Ras oncogene co-activation, BE.EP.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 NIH-3T3 cells. 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.

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.; FIDELIS, V, CARLOS H.; ROCCO, SILVANA A.; BAJGELMAN, MARCIO CHAIM; STINE, ZACHARY; BERINDAN-NEAGOE, IOANA; CALIN, GEORGE A.; BERTELI AMBROSIO, ANDRE LUIS; GOMES DIAS, SANDRA MARTHA. GLS2 is protumorigenic in breast cancers. Oncogene, v. 39, n. 3, p. 690-702, JAN 2020. Web of Science Citations: 0.

QUINTERO, MELISSA; ADAMOSKI, DOUGLAS; DOS REIS, LARISSA MENEZES; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; SOUSA DE OLIVEIRA, KRISHINA RATNA; GONCALVES, KALIANDRA DE ALMEIDA; DIAS, MARILIA MEIRA; CARAZZOLLE, MARCELO FALSARELLA; GOMES DIAS, SANDRA MARTHA. Guanylate-binding protein-1 is a potential new therapeutic target for triple-negative breast cancer. BMC CANCER, v. 17, NOV 7 2017. Web of Science Citations: 8.