Inhibition of the RhoA GTPase Activity Increases Sensitivity of Melanoma Cells to UV Radiation Effects

Autor(es)

Espinha, Gisele ; Osaki, Juliana Harumi ; Costa, Erico Tosoni ; Forti, Fabio Luis

• Tipo de documento: Artigo Científico
• Fonte: OXIDATIVE MEDICINE AND CELLULAR LONGEVITY; v. 2016, p. 14-pg., 2016-01-01.

Resumo

Ultraviolet radiation is the main cause of DNA damage to melanocytes and development of melanoma, one of the most lethal human cancers, which leads to metastasis due to uncontrolled cell proliferation and migration. These phenotypes are mediated by RhoA, a GTPase overexpressed or overactivated in highly aggressive metastatic tumors that plays regulatory roles in cell cycle progression and cytoskeleton remodeling. This work explores whether the effects of UV on DNA damage, motility, proliferation, and survival of human metastatic melanoma cells are mediated by the RhoA pathway. Mutant cells expressing dominant-negative (MeWo-RhoA-N19) or constitutively active RhoA (MeWo-RhoA-V14) were generated and subjected to UV radiation. A slight reduction in migration and invasion was observed in MeWo and MeWo-RhoA-V14 cells but not in MeWo-RhoA-N19 cells, which presented inefficient motility and invasiveness associated with stress fibers fragmentation. Proliferation and survival of RhoA-deficient cells were drastically reduced by UV compared to cells displaying normal or high RhoA activity, suggesting increased sensitivity to UV. Loss of RhoA activity also caused less efficient DNA repair, with elevated levels of DNA lesions such as strand breaks and cyclobutane pyrimidine dimers (CPDs). Thus, RhoA mediates genomic stability and represents a potential target for sensitizing metastatic tumors to genotoxic agents. (AU)

• Processo FAPESP: 11/05822-3 - Investigação da tirosina fosfatase VHR (DUSP3) na resposta a danos do DNA induzidas por radiação ultravioleta em células de melanoma humano
• Beneficiário: Alexsandro dos Santos
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 10/09453-0 - O papel das Rho GTPases na resposta aos danos no DNA induzidos por radiação ionizante do tipo gama
• Beneficiário: Juliana Harumi Osaki
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 08/58264-5 - Papel de GTPases da família Rho e de tirosina fosfatases duais no reparo de danos no DNA
• Beneficiário: Fábio Luis Forti
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 15/03983-0 - Investigação molecular e funcional da interação de DUSP3 com proteínas nucleares: implicações em mecanismos de reparo de DNA
• Beneficiário: Fábio Luis Forti
• Modalidade de apoio: Auxílio à Pesquisa - Regular