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.
| Original language | English |
|---|---|
| Pages (from-to) | 9-19 |
| Number of pages | 11 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 310 |
| DOIs | |
| Publication status | Published - Nov 1 2016 |
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Keywords
- Drug response
- miR-483-3p
- Ovarian carcinoma
- PKC-alpha
- Platinum compounds
ASJC Scopus subject areas
- Medicine(all)
- Toxicology
- Pharmacology
Cite this
PKC-alpha modulation by miR-483-3p in platinum-resistant ovarian carcinoma cells. / Arrighetti, Noemi; Cossa, Giacomo; De Cecco, Loris; Stucchi, Simone; Carenini, Nives; Corna, Elisabetta; Gandellini, Paolo; Zaffaroni, Nadia; Perego, Paola; Gatti, Laura.
In: Toxicology and Applied Pharmacology, Vol. 310, 01.11.2016, p. 9-19.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - PKC-alpha modulation by miR-483-3p in platinum-resistant ovarian carcinoma cells
AU - Arrighetti, Noemi
AU - Cossa, Giacomo
AU - De Cecco, Loris
AU - Stucchi, Simone
AU - Carenini, Nives
AU - Corna, Elisabetta
AU - Gandellini, Paolo
AU - Zaffaroni, Nadia
AU - Perego, Paola
AU - Gatti, Laura
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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.
KW - Drug response
KW - miR-483-3p
KW - Ovarian carcinoma
KW - PKC-alpha
KW - Platinum compounds
UR - http://www.scopus.com/inward/record.url?scp=84983656513&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84983656513&partnerID=8YFLogxK
U2 - 10.1016/j.taap.2016.08.005
DO - 10.1016/j.taap.2016.08.005
M3 - Article
AN - SCOPUS:84983656513
VL - 310
SP - 9
EP - 19
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
ER -