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

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Carboplatin/*pharmacology ; Cullin Proteins/*genetics ; Drug Resistance, Neoplasm/*genetics ; ELAV-Like Protein 1/*genetics ; Saccharomyces cerevisiae/*drug effects ; Saccharomyces cerevisiae/*genetics; Cell Line, Tumor/drug effects ; Chromosomes, Human, Pair 1 ; Cullin Proteins/metabolism ; Cyclopentanes/pharmacology ; Drug Resistance, Fungal/drug effects ; Drug Resistance, Fungal/physiology ; Drug Resistance, Neoplasm/drug effects ; ELAV-Like Protein 1/metabolism ; Female ; Gene Expression Profiling ; Humans ; Mutation ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Pyrimidines/pharmacology ; Ubiquitin-Activating Enzymes/antagonists & inhibitors ; Ubiquitin-Activating Enzymes/genetics ; Ubiquitin-Activating Enzymes/metabolism

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.

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0 (Cullin Proteins)
0 (Cyclopentanes)
0 (ELAV-Like Protein 1)
0 (ELAVL1 protein, human)
0 (Pyrimidines)
BG3F62OND5 (Carboplatin)
EC 6.2.1.45 (Ubiquitin-Activating Enzymes)
EC 6.3.2.- (NAE protein, human)
S3AZD8D215 (pevonedistat)

Date Created: 20151223 Date Completed: 20160725 Latest Revision: 20210402

20250114

PMC4686384

10.1371/journal.pone.0145377

26692264