title: PKC-alpha modulation by miR-483-3p in platinum-resistant ovarian carcinoma cells.
abstract: The occurrence of drug resistance limits the efficacy of platinum compounds in the cure of ovarian carcinoma. Since microRNAs (miRNAs) may contribute to this phenomenon by regulating different aspects of tumor cell response, the aim of this study was to exploit the analysis of expression of miRNAs in platinum sensitive/resistant cells in an attempt to identify potential regulators of drug response. MiR-483-3p, which may participate in apoptosis and cell proliferation regulation, was found up-regulated in 4 platinum resistant variants, particularly in the IGROV-1/Pt1 subline, versus parental cells. Transfection of a synthetic precursor of miR-483-3p in IGROV-1 parental cells elicited a marked up-regulation of the miRNA levels. Growth-inhibition and colony-forming assays indicated that miR-483-3p over-expression reduced cell growth and conferred mild levels of cisplatin resistance in IGROV-1 cells, by interference with their proliferative potential. Predicted targets of miR-483-3p included PRKCA (encoding PKC-alpha), previously reported to be associated to platinum-resistance in ovarian carcinoma. We found that miR-483-3p directly targeted PRKCA in IGROV-1 cells. In keeping with this finding, cisplatin sensitivity of IGROV-1 cells decreased upon molecular/pharmacological inhibition of PKC-alpha. Overall, our results suggest that overexpression of miR-483-3p by ovarian carcinoma platinum-resistant cells may interfere with their proliferation, thus protecting them from DNA damage induced by platinum compounds and ultimately representing a drug-resistance mechanism. The impairment of cell growth may account for low levels of drug resistance that could be relevant in the clinical setting.
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy. Electronic address: Noemi.Arrighetti@istitutotumori.mi.it.
authors.forename: Noemi
authors.initials: N
authors.lastname: Arrighetti
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy. Electronic address: Gia.Cossa@gmail.com.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Cossa
authors.affiliation: Functional Genomics and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy. Electronic address: Loris.Dececco@istitutotumori.mi.it.
authors.forename: Loris
authors.initials: L
authors.lastname: De Cecco
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy. Electronic address: Simone.Stucchi@istitutotumori.mi.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Stucchi
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy. Electronic address: Nives.Carenini@istitutotumori.mi.it.
authors.forename: Nives
authors.initials: N
authors.lastname: Carenini
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy. Electronic address: Elisabetta.Corna@istitutotumori.mi.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Corna
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy. Electronic address: Paolo.Gandellini@istitutotumori.mi.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gandellini
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy. Electronic address: Nadia.Zaffaroni@istitutotumori.mi.it.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy. Electronic address: paola.perego@istitutotumori.mi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy. Electronic address: Laura.Gatti@istitutotumori.mi.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Gatti
mesh_terms: D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D017671:Platinum Compounds / Q000627:therapeutic use*; D051571:Protein Kinase C-alpha / Q000378:metabolism*
chemical_list: C548912:MIRN483 microRNA, human; D035683:MicroRNAs; D017671:Platinum Compounds; D051571:Protein Kinase C-alpha
keywords: Drug response; Ovarian carcinoma; PKC-alpha; Platinum compounds; miR-483-3p