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

Yi Ping Tao, Heng Yan Zhu, Qian Yuan Shi, Cai Xia Wang, Yu Xin Hua, Han Yin Hu, Qi Yin Zhou, Zi Lu Zhou, Ying Sun, Xiao Min Wang, Yu Wang, Ya Ling Zhang, Yan Jun Guo, Zi Ying Wang, Xuan Che, Chun Wei Xu, Xian Chao Zhang, Michal Heger, Su Ping Tao, Xin ZhengYing Xu, Lei Ao, Ai Jun Liu, Sheng Bing Liu*, Shu Qun Cheng*, Wei Wei Pan*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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. 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.

Original languageEnglish
Pages (from-to)3491-3502
Number of pages12
JournalOncogene
Volume42
Issue number47
DOIs
Publication statusPublished - 17 Nov 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Funding

We thank Yuan-Yuan Gao, Jing-Ya Zhong, Jing-Jian Dong, and Li-Li Shi for technical assistance, Dr. Kun-Liang Guan for the CRISPR/Cas9 plasmid, Dr. Fa-Xin Yu for the liver tissues of MST knockout mice, and Dr. Heng-Yu Fan for the IOSE cells. This work was supported by Key Laboratory of Medical Electronics and Digital Health of Zhejiang Province and Engineering Research Center of Intelligent Human Health Situation Awareness of Zhejiang Province, Jiaxing University, 314001, China. This work was further supported by the Jiaxing talent pioneer innovation team, Jiaxing. This work was further supported by grants from National Natural Science Foundation of China (31871402) and The Natural Science Foundation of Zhejiang Province (LY21H160047, LGD21H160003, LQ23C070001, LY17H160060, Z20H160031, LGF20H160031, Z20H160031, LGF20H160031). This work was further supported by grants from National College Student Innovation and Entrepreneurship Training Program (222022R7034, 202110354015, 2021R417023, 202113291002, 202113291003) and Zhejiang Provincial Foreign Expert Grant (12.2018). This work was further supported by Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics (12.2019). This work was further supported by the Dutch Cancer Foundation (KWF, project 10666) and The Top-level Talent Project of Zhejiang Province. This work was supported by the Jiaxing talent pioneer innovation team (6.2021).

FundersFunder number
Jiaxing talent pioneer innovation team
Key Laboratory of Medical Electronics and Digital Health of Zhejiang Province and Engineering Research Center of Intelligent Human Health Situation Awareness of Zhejiang Province
Top-level Talent Project of Zhejiang Province
Zhejiang Provincial Foreign Expert12.2019, 12.2018
Cancer Couch Foundation
National Natural Science Foundation of China31871402
KWF Kankerbestrijding10666
Natural Science Foundation of Zhejiang ProvinceLY17H160060, LGF20H160031, LQ23C070001, LY21H160047, Z20H160031, LGD21H160003
National College Students Innovation and Entrepreneurship Training Program202113291003, 2021R417023, 202110354015, 202113291002, 222022R7034
Jiaxing University314001

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