Metformin reverses drug-resistance of ovarian cancer cells to cisplatin by inhibiting p38 mitogen-activated protein kinase signaling pathway / 肿瘤

ABSTRACT

Objective: To investigate whether metformin can reverse drug-resistance of ovarian cancer cells to cisplatin, and explore its underlying mechanism. Methods: Cisplatin-resistant ovarian cancer cells C1 3K and CP70 were used in this study. The small interfering RNAs (siRNAs) targeting excision repair cross-complemention 1 (ERCC1) gene were synthesized and transfected into C1 3K and CP70 cells, respectively. The change of cisplatin-resistance of C1 3K and CP70 cells was detected by cell count kit-8 (CCK-8) assay after metformin treatment and ERCC1 siRNA transfection. The expressions of ERCC1 mRNA in C13K and CP70 cells treated with different concentrations of metformin were detected by real-time fluorescent quantitative-PCR. The activation of AMP-activated protein kinase (AMPK) and suppression of p38 mitogen-activated protein kinase (p38MAPK) in C1 3K and CP70 cells after metformin treatment were evaluated by Western blotting. Then the expression level of ERCC1 protein in C1 3K and CP70 cells treated with metformin (combined with Compound C, a blocking agent of AMPK signaling pathway, or p38MAPK siRNA transfection) or SB203580 (an inhibitor of p38MAPK signaling pathway) was detected by Western blotting. Results: Metformin could reverse drug-resistance of C13K and CP70 cells to cisplatin (P 0.05). Conclusion: Metformin may reverse the drug-resistance of cisplatin-resistant ovarian cancer cells to cisplatin. This effect of metformin may be due to the inhibition of p38MAPK signaling pathway and the downregulation of ERCC1 gene expression in ovarian cancer cells.