title: Chemogenomic Study of Carboplatin in Saccharomyces cerevisiae: Inhibition of the NEDDylation Process Overcomes Cellular Resistance Mediated by HuR and Cullin Proteins.
abstract: 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 NEDDylation 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.
authors.affiliation: Departamento de Tecnologia Bioquímico-Farmacêutica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo-USP, Brazil.
authors.forename: Graziele Fonseca
authors.initials: GF
authors.lastname: de Sousa
authors.affiliation: Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo-USP, Brazil.
authors.forename: Maira de Assis
authors.initials: Mde A
authors.lastname: Lima
authors.affiliation: Departamento de Tecnologia Bioquímico-Farmacêutica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo-USP, Brazil.
authors.forename: Débora Fernandes
authors.initials: DF
authors.lastname: Custodio
authors.affiliation: Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo-USP, Brazil.
authors.forename: Vanessa Morais
authors.initials: VM
authors.lastname: Freitas
authors.affiliation: Departamento de Tecnologia Bioquímico-Farmacêutica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo-USP, Brazil.
authors.forename: Gisele
authors.initials: G
authors.lastname: Monteiro
mesh_terms: D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002878:Chromosomes, Human, Pair 1; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology; D025141:Drug Resistance, Fungal / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D000067780:ELAV-Like Protein 1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics*; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D044842:Cullin Proteins; D003517:Cyclopentanes; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D011743:Pyrimidines; D016190:Carboplatin; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat