Smad7 drives cisplatin resistance in ovarian cancer via a PRMT5-dependent mechanism
Acquired cisplatin resistance poses a major challenge in ovarian cancer management. This study investigated the role of protein arginine methyltransferase 5 (PRMT5) in this context. Using cisplatin-resistant ovarian cancer cell lines (A2780/DDP and SKOV3/DDP), we found that PRMT5 knockdown significantly inhibited cell proliferation, colony formation, migration, and invasion, while promoting apoptosis. Mechanistically, co-immunoprecipitation assays revealed that PRMT5, in complex with MEP50, interacts with and specifically methylates Smad7 at the R57 site in vitro. This methylation event was essential for activating the STAT3 signaling pathway and driving the observed malignant phenotypes. Consistent with a key oncogenic role for Smad7, in vivo knockdown of Smad7 in a xenograft mouse model markedly suppressed tumor growth and downregulated markers of proliferation (Ki67), invasion (MMP9, N-cadherin), while upregulating the tumor suppressor E-cadherin. In conclusion, our work identifies Smad7 as a critical driver of cisplatin resistance in vivo and delineates a novel in vitro mechanism whereby PRMT5 promotes oncogenic signaling through R57 methylation of Smad7. This PRMT5-Smad7 axis presents a promising therapeutic target for overcoming cisplatin resistance in ovarian cancer.