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.