S1PR1 regulates ovarian cancer cell senescence through the PDK1-LATS1/2-YAP pathway

Abstract

Abstract 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, which concurred with cell cycle arrest in the G1/S phase. S1PR1 deletion enhanced cisplatin-induced ovarian cancer cell senescence. Treatment of ovarian cancer cells with sphingosine-1-phosphate (S1P) led to increased expression of 3-phosphatidylinositol-dependent protein kinase 1 (PDK1), decreased expression of large tumor suppressor 1/2 (LATS1/2), and increased activity of the yes-associated protein (YAP). Opposite results were obtained in S1PR1-knockout or pharmacological inhibition in ovarian cancer cells. LATS1/2 inactivation caused by S1PR1 deletion increased YAP expression, inhibited senescence, and lead to increased S1PR1 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.