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Interface of post-translational glycosylation and ER stress in melanoma: target to cancer cell sensitization to chemotherapeutic agents?

Grant number: 11/05038-0
Support type:Scholarships in Brazil - Master
Effective date (Start): August 01, 2011
Effective date (End): March 31, 2013
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Roger Chammas
Grantee:Luiza Helena Madia Lourenço
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


Melanoma is the most lethal skin cancer, despite being less prevalent. Due to its lethality and resistance to a variety of known chemotherapeutic drugs, studies on melanoma are paramount. Tumor cells in general, and melanoma cells particularly, commonly present a disturbed metabolic rate, e.g, altered metabolism of reactive oxygen species and increased rates of protein synthesis. Altogether these perturbations would often trigger the Unfolded Protein Response (UPR), when a tolerance threshold is reached. Previous data from our laboratory showed that GRP78 and GADD153 are not constitutively expressed in tumorigenic cells. However, when exposed to an ER stressor, such as tunicamycin, tumorigenic cells were more sensitive, accumulating larger amounts of both ER stress markers. These results suggested us that melanoma cells live in unstable equilibrium, closer to the UPR threshold. This state is likely maintained by adaptation mechanisms that potentially involve co- and post-translational protein alterations. Glycosylation of tumor cells are commonly altered. Among the known alterations of N-glycosylation it is the overexpression of MGAT5. Our hypothesis is that the expression of either MGAT5 or its paralog MGAT5B is part of an adaptive response to reticulum stress, and on doing so they would serve as targets for sensitization of melanoma cells to the UPR. Inhibition of their expression would then be potentially useful for a combined treatment of melanoma cells with chemotherapeutic agents. (AU)