Activation of the Endoplasmic reticulum stress pathway as a potential chemosensitizing agent in cisplatin-induced cell death.

• Grant number: 07/05975-9
• Support Opportunities: Scholarships in Brazil - Master
• Start date: March 01, 2008
• End date: July 31, 2009
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Roger Chammas
• Grantee: Renata de Freitas Saito
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 98/14247-6 - Center for Research on Cell-Based Therapy, AP.CEPID

Abstract

Among skin cancers, melanoma presents the highest letality, despite its relatively low incidence. Different from every other tumor, melanoma incidence is increasing at a very high rate in the last 20 years. When diagnosed at late stages, melanoma seems resistant to chemotherapy. The molecular bases of such chemoresistance are now being unveiled, opening new perspectives for the treatment of the disease. Here we intend to evaluate the use of curcumin, as a potential chemosensitizing drug, in cisplatin-induced melanoma cell death. The mechanisms of action of curcumin will be studied, emphasizing aspects of an endoplasmic reticulum stress response, namely the unfolded protein response (UPR), which leads to activation of GADD153 and thus apoptosis. Endoplasmic reticulum stress will be induced in control conditions using tunicamycin and thapsigargin. Once the conditions of ER stress are defined, activation of GADD153 and induction of cell death by curcumin, either alone or in combination with cisplatin, will then be evaluated. Knockdown assays with siRNA for GADD153 will allow for evaluation of the role of GADD153 in the stress response. These parameters will be also useful for exploring a possible association with this pathway with glycosphingolipids produced by melanoma cells, such as the disialoganglioside GD3, which is considered pro-apoptotic for normal cells, but it seems ineffective for tumor cells.