Evaluation of prohibitin participation in the four main pathways of melanoma development

• Grant number: 08/11505-8
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): May 01, 2009
• Effective date (End): September 30, 2012
• Field of knowledge: Biological Sciences - Biology
• Principal Investigator: Roger Chammas
• Grantee: Tharcisio Citrangulo Tortelli Junior
• Home Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 98/14247-6 - Center for Research on Cell-Based Therapy, AP.CEPID

Abstract

The incidence of melanomas has grown world-wide. Besides representing a potential problem of public health for its increasing incidence, melanomas are tumors of difficult treatment, especially when diagnosed in advanced phases. The clinical objective response rate does not exceed 30% in these cases. The molecular bases of chemoresistance are not completely clarified and their understanding will be useful for the delineation of chemosensitization strategies. Among the four main pathways of melanoma development are: activation of AKT and MAPK pathways, blocking of the p16INK4a pathway and translocation of ²-catenin from the plasma membrane into the nucleus. In previous studies, we observed that the treatment of a human metastatic melanoma cell line with the chemotherapeutic agent cisplatin induced the accumulation of prohibitin in the surviving cells. Prohibitin is ubiquitously expressed molecule in most cells. There is evidence that the nuclear form is involved with the process of cell death and inhibition of E2F1, while the cytoplasmic form seems to act as mitochondrial chaperone, guaranteeing its homeostasis. In addition, prohibitin may be interfering in the four main pathways of melanoma development. Studies in other cell types showed that prohibitin can activate the MAPK pathway, be phosphorylated by AKT, inhibit the activity of p16INK4a and its knock-out by siRNA can relocate ²-catenin to the plasma membrane. The aim of this project is to evaluate the participation of prohibitin in the four main pathways of melanoma development (p16INK4a, ²-catenina, AKT and MAPK) and check the impact of loss of prohibitin in parameters of response to cell death induced by chemotherapy used in the treatment of human melanoma. (AU)