Evaluating disialoganglioside compartmentalisation role in human melanoma lineage on resistance and sensitization to chemotherapy-induced death

• Grant number: 06/01519-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: March 01, 2007
• End date: February 28, 2009
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Roger Chammas
• Grantee: Andréia Hanada Otake
• 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

Melanoma is a neoplasm that originates from melanocytes. These cells are responsible for pigment production and localize mainly in the basal layer of epidermis. Melanomas have poor response to chemotherapy and accumulate molecular alterations during treatment. Tumor cells show different alterations in the expression and/or molecule function that controls the proliferation and cell death. Loss of expression of the product of the CDKN2A gene and loss of tumor suppressor gene PTEN promote melanoma development. Moreover, melanoma cells accumulate dissialogangliosides like GD3 and derivatives. Gangliosides are a family of sialic acid-containing glycosphingolipids mainly located in the outer leaflet of the plasma membrane. The exact function of this accumulation is not clear yet. Dissialogangliosides, as GD3, seem to modulate cell death, while other gangliosides can modulate proliferative response. Data of our group have shown that melanocytes, that express GD3 and its derivatives, are more sensitive to the chemotherapy-induced cell death, as cisplatin and vinblastine. Moreover, glucosylceramide-synthase inhibition showed that the cells treated with vinblastine lose its sensitivity to this drug. The translocation of dissialialogangliosides, as the GD3, for the mitochondria contributes for the death process. The impairment of microtubule and the unfolded proteins response of the endoplasmic reticulum seem to be important for the GD3 relocation to mitochondria. The subcellular localization of dissialogangliosides and the modulation of their expression, using interference RNA for blocking GD3-synthase expression, in human melanoma cells will be explored in this project. Moreover, the molecular mechanisms involved in the process of drug-induced cell death will be determined.