miR-512-3p/RPS6KA2 Axis Regulates Cisplatin Resistance in Ovarian Cancer via Autophagy and FerroptosisOA
Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance in ovarian cancer is not well characterized.This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer,particularly in relation to cisplatin resistance.Methods:The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR,immunofluorescence staining,immunohistochemistry,and western blotting.Prognostic associations were conducted using the Kaplan-Meier Plotter database.Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity.Ferroptosis-related parameters,including intracellular iron content,glutathione(GSH)levels,reactive oxygen species(ROS)generation,and mitochondrial membrane potential,were measured to determine ferroptotic changes.In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents.Results:Using ovarian cancer cell lines and clinical tissue samples,we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts.Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance.Mechanistically,RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin(PI3K-AKT-mTOR)signaling pathway,which in turn increased sensitivity to cisplatin.Additionally,RPS6KA2 facilitated ferroptosis,contributing to its tumor-suppressive function.miR-512-3p was identified as a negative regulator of RPS6KA2,driving cisplatin resistance through suppression of RPS6KA2 expression.In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models.Conclusion:These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.
Jianfa Wu;Huang Chen;Sihong Wang;Lei Peng;Xiaoying Hu;Zhou Liu
Department of Gynecology,Shanghai University of Medicine&Health Sciences Affiliated Zhoupu Hospital,Shanghai,201318,China Department of Gynecology,Shanghai University of Medicine&Health Sciences,Shanghai,201318,China Department of Integrated Traditional Chinese and Western Medicine Clinical Practice,Shanghai University of Traditional Chinese Medicine,Shanghai,200032,ChinaDepartment of Integrated Traditional Chinese and Western Medicine Clinical Practice,Shanghai University of Traditional Chinese Medicine,Shanghai,200032,ChinaDepartment of Gynecology,Shanghai University of Medicine&Health Sciences Affiliated Zhoupu Hospital,Shanghai,201318,China Department of Gynecology,Shanghai University of Medicine&Health Sciences,Shanghai,201318,ChinaDepartment of Gynecology,Shanghai University of Medicine&Health Sciences Affiliated Zhoupu Hospital,Shanghai,201318,China Department of Gynecology,Shanghai University of Medicine&Health Sciences,Shanghai,201318,ChinaDepartment of Gynecology,Shanghai University of Medicine&Health Sciences Affiliated Zhoupu Hospital,Shanghai,201318,China Department of Gynecology,Shanghai University of Medicine&Health Sciences,Shanghai,201318,ChinaDepartment of Gynecology,Shanghai University of Medicine&Health Sciences Affiliated Zhoupu Hospital,Shanghai,201318,China Department of Gynecology,Shanghai University of Medicine&Health Sciences,Shanghai,201318,China
医药卫生
RPS6KA2autophagyovarian cancerferroptosischemoresistance
《Oncology Research》 2026 (1)
P.568-597,30
supported by the Academic Leader Training Programof Pudong New Area Health System in Shanghai(Grant No.PWRd2021-13)Shanghai Municipal Health Commission(Grant No.202340094).
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