细胞衰老会阻止各种癌基因的激活。因此，诱导衰老是干扰肿瘤细胞重要过程的潜在有效策略。 1-磷酸鞘氨醇受体 1 (S1PR1) 与多种癌症类型有关，包括卵巢癌。 S1PR1 调节卵巢癌细胞衰老的机制目前尚不清楚。在这项研究中，我们证明S1PR1在人卵巢癌组织和细胞系中高表达。 S1PR1缺失抑制卵巢癌细胞的增殖和迁移。 S1PR1缺失促进卵巢癌细胞衰老并使卵巢癌细胞对顺铂化疗敏感。卵巢癌细胞暴露于 1-磷酸鞘氨醇 (S1P) 会增加 3-磷脂酰肌醇依赖性蛋白激酶 1 (PDK1) 的表达，降低大肿瘤抑制因子 1/2 (LATS1/2) 的表达，并诱导Yes相关蛋白（p-YAP）。在药物抑制后，S1PR1 敲除细胞中获得了相反的结果。在 S1PR1 缺陷的卵巢癌细胞中沉默 LATS1/2 后，衰老受到抑制，并且 S1PR1 表达随着 YAP 表达而增加。通过染色质免疫沉淀证实了 YAP 对 S1PR1 的转录调节。因此，S1PR1-PDK1-LATS1/2-YAP 通路通过 YAP 介导的反馈回路调节卵巢癌细胞衰老。 S1PR1 构成了诱导卵巢癌细胞衰老的药物靶点。对 S1PR1-PDK1-LATS1/2-YAP 信号轴的药物干预可能会增强标准化疗的疗效。© 2023。作者。

Cell senescence deters the activation of various oncogenes. Induction of senescence is, therefore, a potentially effective strategy to interfere with vital processes in tumor cells. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in various cancer types, including ovarian cancer. The mechanism by which S1PR1 regulates ovarian cancer cell senescence is currently elusive. In this study, we demonstrate that S1PR1 was highly expressed in human ovarian cancer tissues and cell lines. S1PR1 deletion inhibited the proliferation and migration of ovarian cancer cells. S1PR1 deletion promoted ovarian cancer cell senescence and sensitized ovarian cancer cells to cisplatin chemotherapy. Exposure of ovarian cancer cells to sphingosine-1-phosphate (S1P) increased the expression of 3-phosphatidylinositol-dependent protein kinase 1 (PDK1), decreased the expression of large tumor suppressor 1/2 (LATS1/2), and induced phosphorylation of Yes-associated protein (p-YAP). Opposite results were obtained in S1PR1 knockout cells following pharmacological inhibition. After silencing LATS1/2 in S1PR1-deficient ovarian cancer cells, senescence was suppressed and S1PR1 expression was increased concomitantly with YAP expression. Transcriptional regulation of S1PR1 by YAP was confirmed by chromatin immunoprecipitation. Accordingly, the S1PR1-PDK1-LATS1/2-YAP pathway regulates ovarian cancer cell senescence and does so through a YAP-mediated feedback loop. S1PR1 constitutes a druggable target for the induction of senescence in ovarian cancer cells. Pharmacological intervention in the S1PR1-PDK1-LATS1/2-YAP signaling axis may augment the efficacy of standard chemotherapy.© 2023. The Author(s).