Rationale: Cisplatin derivatives are first-line chemotherapeutic agents for epithelial ovarian cancer. However, chemoresistance remains a major hurdle for successful therapy and the underlying molecular mechanisms are poorly understood at present./nMethods: RNA sequencing of organoids (PDO) established from cisplatin-sensitive and -resistant ovarian cancer tissue samples was performed. Glucose metabolism, cell senescence, and chemosensitivity properties were subsequently examined. Immunoprecipitation, mass spectrometry, Fӧrster resonance energy transfer-fluorescence lifetime imaging (FRET-FLIM), luciferase reporter assay, ChIP and animal experiments were conducted to gain insights into the specific functions and mechanisms of action of the serine/threonine kinase, Aurora-A, in ovarian cancer./nResults: Aurora-A levels were significantly enhanced in cisplatin-resistant PDO. Furthermore, Aurora-A promoted chemoresistance through suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Mechanistically, Aurora-A bound directly to the transcription factor sex determining region Y-box 8 (SOX8) and phosphorylated the Ser327 site, in turn, regulating genes related to cell senescence and glycolysis, including hTERT, P16, LDHA and HK2, through enhancement of forkhead-box k1 (FOXK1) expression./nConclusions: Aurora-A regulates cell senescence and glucose metabolism to induce cisplatin resistance by participating in the SOX8/FOXK1 signaling axis in ovarian cancer. Our collective findings highlight a novel mechanism of cisplatin resistance and present potential therapeutic targets to overcome chemoresistance in ovarian cancer.

中文翻译：

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Aurora-A / SOX8 / FOXK1信号轴通过抑制细胞衰老和诱导卵巢癌类器官和细胞中的糖代谢来促进化学抗性。

理由：顺铂衍生物是上皮性卵巢癌的一线化疗药物。然而，化学抗药性仍然是成功治疗的主要障碍，目前尚不清楚其潜在的分子机制。/n方法：对顺铂敏感且耐药的卵巢癌组织样品建立的类器官（PDO）进行RNA测序。随后检查了葡萄糖的代谢，细胞衰老和化学敏感性。进行了免疫沉淀，质谱，菲斯特共振能量转移-荧光寿命成像（FRET-FLIM），萤光素酶报告基因测定，ChIP和动物实验，以深入了解丝氨酸/苏氨酸激酶Aurora-A的特定功能和作用机理，在卵巢癌中。结果：耐顺铂的PDO中Aurora-A水平显着提高。此外，Aurora-A通过抑制细胞衰老和诱导卵巢癌类器官和细胞中的糖代谢促进化学抗性。机械上，Aurora-A直接与转录因子性别决定区Y-box 8（SOX8）结合并磷酸化Ser327位点，进而通过增强来调节与细胞衰老和糖酵解相关的基因，包括hTERT，P16，LDHA和HK2前叉箱k1（FOXK1）表达式的表达。/n结论：Aurora-A通过参与卵巢癌的SOX8 / FOXK1信号轴来调节细胞衰老和葡萄糖代谢，从而诱导顺铂耐药。我们的集体发现强调了顺铂耐药性的新机制，并提出了克服卵巢癌化学耐药性的潜在治疗靶标。