S1PR1 regulates ovarian cancer cell senescence through the PDK1-LATS1/2-YAP pathway
Author:
Tao Yi-Ping, Zhu Heng-Yan, Shi Qian-Yuan, Wang Cai-Xia, Hua Yu-Xin, Hu Han-Yin, Zhou Qi-Yin, Zhou Zi-Lu, Sun Ying, Wang Xiao-MinORCID, Wang Yu, Zhang Ya-Ling, Guo Yan-Jun, Wang Zi-Ying, Che Xuan, Xu Chun-Wei, Zhang Xian-Chao, Heger Michal, Tao Su-Ping, Zheng Xin, Xu Ying, Ao Lei, Liu Ai-Jun, Liu Sheng-BingORCID, Cheng Shu-QunORCID, Pan Wei-WeiORCID
Abstract
AbstractCell 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.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Genetics,Molecular Biology
Reference55 articles.
1. Lisio MA, Fu L, Goyeneche A, Gao ZH, Telleria C. High-grade serous ovarian cancer: basic sciences, clinical and therapeutic standpoints. Int J Mol Sci. 2019;20:952. 2. Shen L, Xia M, Zhang Y, Luo H, Dong D, Sun L. Mitochondrial integration and ovarian cancer chemotherapy resistance. Exp Cell Res. 2021;401:112549. 3. Keyvani V, Farshchian M, Esmaeili SA, Yari H, Moghbeli M, Nezhad SK, et al. Ovarian cancer stem cells and targeted therapy. J Ovarian Res. 2019;12:120. 4. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685–705. 5. Wang Z, Liu H, Xu C. Cellular senescence in the treatment of ovarian cancer. Int J Gynecol Cancer. 2018;28:895–902.
|
|