Simvastatin Restores Cisplatin Sensitivity by Suppressing the Caveolin-1-Mediated PI3K/AKT Signaling Pathway in Cisplatin-Resistant Cervical Cancer Cells.

Cervical cancer treatment is often hindered by the emergence of cisplatin (DDP) resistance. Increasing evidence has indicated that statins possess anti-tumor and chemosensitization potential beyond their lipid-lowering effects. Statin utilization is found to be significantly linked to decreased cervical cancer incidence and mortality. However, whether statins affect chemosensitivity to cisplatin in cisplatin-resistant cervical cancer remains to be clarified. In cervical cancer cisplatin-resistant cell lines (SiHa-DDP and C33a-DDP) constructed from their parental cells, the effects of seven statins (simvastatin, fluvastatin, pitavastatin, lovastatin, atorvastatin, rosuvastatin, and pravastatin) on cell viability in cisplatin-resistant cells and corresponding parental cells were assessed using the CCK-8 assay. Compared with parental counterparts, the IC50 values of seven statin drugs were markedly elevated in cells exhibiting cisplatin resistance. Simvastatin significantly enhanced the efficacy of cisplatin in cisplatin-resistant cervical cancer cells, demonstrating a synergistic anti-cancer effect (CI < 1). Combined therapy using simvastatin and cisplatin inhibited cell viability and migration while promoting cell apoptosis. Mechanistically, simvastatin downregulated protein expressions of caveolin-1 (CAV1), PI3K, and p-AKT. CAV1 knockdown in SiHa-DDP and C33a-DDP cells markedly increased cisplatin sensitivity, confirming its critical role in chemoresistance. Rescue experiments showed that CAV1 overexpression partially counteracted the inhibitory effects of simvastatin. In vivo, compared with monotherapies, simvastatin combined with cisplatin treatment markedly suppressed tumor growth, reduced CAV1 protein expression, decreased the percentage of Ki67-positive cells and promoted apoptosis. In all, simvastatin enhanced cisplatin sensitivity by suppressing the CAV1-mediated PI3K/AKT pathway involvement in the development of cisplatin resistance in cervical cancer cells. These findings reveal a novel mechanism in cervical cancer cells resistant to cisplatin by which simvastatin may serve as a potential adjuvant to improve the therapeutic efficacy of cisplatin-based chemotherapy.