Olaparib increases chemosensitivity by upregulating miR-125a-3p in ovarian cancer cells

Abstract

Abstract Objective Ovarian cancer has the highest mortality rate among malignant gynecological tumors. PolyADP-ribose polymerase (PARP) inhibitor maintenance therapy is the standard treatment. Olaparib is a widely used oral PARP inhibitor for tumors with BRCA mutations, but its effect and molecular mechanism in non-BRCA-mutated tumors remain unclear. Methods The antitumor effect of cisplatin alone or in combination with olaparib was analyzed in an ovarian cancer subcutaneous transplantation tumor model in nude mice. miRNA expression was analyzed through an miRNA array and real-time PCR. The effect of miR-125a-3p on proliferation in non-BRCA-mutated A2780 and OVCAR-3 ovarian cancer cells was detected with cell counting kit-8. Changes in cell invasion and migration ability were detected via cell scratch assays and Transwell assays. β-Galactosidase (SA-β-Gal) was used to detect expression changes related to cellular senescence. Cell cycle changes were detected by flow cytometry, and the expression of DNA damage repair proteins was detected by western blotting. Results In vivo, cisplatin plus olaparib significantly reduced tumor volume in mice subjected to subcutaneous tumor transplantation (A2780 and OVCAR-3 cells) (p < 0.01) and inhibited tumor growth. Additionally, olaparib induced senescence in A2780 and OVCAR-3 cells by upregulating miRNA-125a-3p. miRNA-125a-3p overexpression significantly inhibited invasion and migration in A2780 and OVCAR-3 cells. The cell cycle was blocked in G0/G1 phase, and the expression of the DNA damage protein gamma-H2AX (γ-H2AX) increased. Transfection of miRNA-125a-3p inhibitors reversed these phenotypes. Conclusions Olaparib induces DNA damage and senescence in ovarian cancer cells by upregulating miR-125a-3p expression, improving therapeutic sensitivity.