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Study of the antioxidant response in tumor cells KRAS and BRAF-mutated by the analysis of expression patterns of cytoprotective genes regulated by Nrf2

Grant number: 14/04246-7
Support type:Scholarships in Brazil - Master
Effective date (Start): May 01, 2014
Effective date (End): March 08, 2016
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal researcher:Anamaria Aranha Camargo
Grantee:Juliana Quintanilha Martins
Home Institution: Laboratório de Biologia Molecular e Genômica. Instituto Ludwig de Pesquisa sobre o Câncer (ILPC). São Paulo , SP, Brazil

Abstract

Colorectal cancer is one of the most prevalent cancer types in the world, with annual incidence estimated in 1.200.000 new cases and mortality estimated in 609.000 victims. Unfortunately, 20% of patients with colorectal cancer are diagnosed with advanced metastatic disease, and the 5-year overall survival rate for this patients is 12%. Despite the new therapeutic options based on the use of antibodies anti-EGFR for metastatic colorectal cancer, only a small percentage of patients benefits from it, due to the development of resistance mechanisms by the tumor cell associated to the presence of mutations in the KRAS oncogene. Activating mutations in the KRAS oncogene occur in 35-45% of colorectal tumors, and were recently associated to the occurrence of mitochondrial dysfunction, to the increase of aerobic glycolysis and of intracellular levels of reactive oxygen species (ROS). Evidences indicate that the increase of ROS induced by KRAS(mut) is functionally relevant to the malignant transformation, but excessive amounts of ROS cause oxidative injuries to the cell, and therefore the maintenance of ROS homeostasis is crucial to the growth and survival of the tumor cell. The antioxidant citoprotective response is mainly regulated by the complex Nrf2-Keap1. Recently, it was demonstrated that the expression of the oncogenic alleles of KRAS, BRAF or Myc in tumor murine lineages results in the upregulation of Nrf2 transcription, which leads to the reduction of intracellular levels of ROS and to the reestablishment of redox balance in the tumor cell. Moreover, it was demonstrated that the absence of Nrf2 is capable of preventing the RAS-induced tumorigenesis in vivo, highlighting the dependence of tumors with alterations in RAS to the antioxidant response mediated by Nrf2. The dependence of tumor cells with mutations in KRAS to the antioxidant response can be explored as a powerful therapeutic approach for patients with metastatic colorectal cancer resistant to the anti-EGFR treatment, and, for that, it is of remarkable relevance a better characterization of cellular adaptation mechanisms of tumor cells to oxidative stress. In this context, this project aims to conduct an exploratory analysis of differential expression of cytoprotective genes regulated by the transcription factor Nrf2 in wild-type and KRAS and BRAF-mutated colon cancer lineages, aiming to the identification of genes involved in the antioxidant response that are differentially expressed in colorectal tumors and that may represent new targets for a possible therapeutic intervention with pro-oxidant drugs.