Chemogenomic Study of Carboplatin in Saccharomyces cerevisiae: Inhibition of the NEDDylation Process Overcomes Cellular Resistance Mediated by HuR and Cullin Proteins

Autor(es)

de Sousa, Graziele Fonseca ^[1] ; Lima, Maira de Assis ^[2] ; Custodio, Debora Fernandes ^[1] ; Freitas, Vanessa Morais ^[2] ; Monteiro, Gisele ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut, Dept Tecnol Bioquim Farmaceut, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Biol Celular Desenvolvimento, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 10, n. 12 DEC 21 2015.
• Citações Web of Science: 9

Resumo

The use of carboplatin in cancer chemotherapy is limited by the emergence of drug resistance. To understand the molecular basis for this resistance, a chemogenomic screen was performed in 53 yeast mutants that had previously presented strong sensitivity to this widely used anticancer agent. Thirty-four mutants were responsive to carboplatin, and from these, 21 genes were selected for further studies because they have human homologues. Sixty percent of these yeast genes possessed human homologues which encoded proteins that interact with cullin scaffolds of ubiquitin ligases, or whose mRNA are under the regulation of Human antigen R (HuR) protein. Both HuR and cullin proteins are regulated through NED-Dylation post-translational modification, and so our results indicate that inhibition of this process should sensitise resistant tumour cells to carboplatin. We showed that treatment of a tumour cell line with MLN4924, a NEDDylation inhibitor, overcame the resistance to carboplatin. Our data suggest that inhibition of NEDDylation may be a useful strategy to resensitise tumour cells in patients that have acquired carboplatin resistance. (AU)

• Processo FAPESP: 11/04173-1 - Identificação de alvos moleculares associados à resistência aos antitumorais Carboplatina e análogos de Rebecamicina usando Saccharomyces cerevisiae como modelo celular
• Beneficiário: Graziele Fonseca de Sousa
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 09/01303-1 - Caracterização de ORFs de função desconhecida envolvidas na resposta antioxidante em Saccharomyces cerevisiae
• Beneficiário: Gisele Monteiro
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 15/07749-2 - Engenharia de proteínas e comparação de sistemas microbianos de expressão do biofármaco L-asparaginase
• Beneficiário: Gisele Monteiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular