title: Translational regulation of the mRNA encoding the ubiquitin peptidase USP1 involved in the DNA damage response as a determinant of Cisplatin resistance.
abstract: Cisplatin (cis-diaminedichloroplatin (II), CDDP) is part of the standard therapy for a number of solid tumors including Non-Small-Cell Lung Cancer (NSCLC). The initial response observed is in most cases only transient and tumors quickly become refractory to the drug. Tumor cell resistance to CDDP relies on multiple mechanisms, some of which still remain unknown. In search for such mechanisms, we examined the impact of CDDP on mRNA translation in a sensitive and in a matched resistant NSCLC cell line. We identified a set of genes whose mRNAs are differentially translated in CDDP resistant vs. sensitive cells. The translation of the mRNA encoding the Ubiquitin-Specific Peptidase 1 (USP1), a Ubiquitin peptidase with important function in multiple DNA repair pathways, is inhibited by CDDP exposure in the sensitive cells, but not in the resistant cells. This lack of down-regulation of USP1 expression at the translational level plays a primary role in CDDP resistance since inhibition of USP1 expression or activity by siRNA or the small molecule inhibitor ML323, respectively is sufficient to re-sensitize resistant cells to CDDP. We involved the USP1 mRNA translation as a major mechanism of CDDP resistance in NSCLC cells and suggest that USP1 could be evaluated as a candidate predictive marker and as a therapeutic target to overcome CDDP resistance. More generally, our results indicate that analysis of gene expression at the level of mRNA translation is a useful approach to identify new determinants of CDDP resistance.
authors.affiliation: a Inserm Unit 981, DHU TORINO; Gustave Roussy and University Paris Sud ; Villejuif , France.
authors.forename: Tony
authors.initials: T
authors.lastname: Sourisseau
authors.affiliation: a Inserm Unit 981, DHU TORINO; Gustave Roussy and University Paris Sud ; Villejuif , France.
authors.forename: Carole
authors.initials: C
authors.lastname: Helissey
authors.affiliation: a Inserm Unit 981, DHU TORINO; Gustave Roussy and University Paris Sud ; Villejuif , France.
authors.forename: Céline
authors.initials: C
authors.lastname: Lefebvre
authors.affiliation: a Inserm Unit 981, DHU TORINO; Gustave Roussy and University Paris Sud ; Villejuif , France.
authors.forename: Florence
authors.initials: F
authors.lastname: Ponsonnailles
authors.affiliation: a Inserm Unit 981, DHU TORINO; Gustave Roussy and University Paris Sud ; Villejuif , France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Malka-Mahieu
authors.affiliation: a Inserm Unit 981, DHU TORINO; Gustave Roussy and University Paris Sud ; Villejuif , France.
authors.forename: Ken A
authors.initials: KA
authors.lastname: Olaussen
authors.affiliation: a Inserm Unit 981, DHU TORINO; Gustave Roussy and University Paris Sud ; Villejuif , France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.affiliation: b Institut Curie ; Center de Recherche ; Orsay , France.|c CNRS UMR3348 ; Orsay , France.|d University Paris-Sud XI ; Orsay , France.|e PSL research university ; Paris , France.
authors.forename: Stephan
authors.initials: S
authors.lastname: Vagner
authors.affiliation: a Inserm Unit 981, DHU TORINO; Gustave Roussy and University Paris Sud ; Villejuif , France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C579228:USP1 protein, human; D064570:Ubiquitin-Specific Proteases; D002945:Cisplatin
keywords: 5′ untranslated region; cisplatin resistance; deubiquitination; lung cancer; monoubiquitination; translation
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