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RIP1 promotes proliferation through G2/M checkpoint progression and mediates cisplatin-induced apoptosis and necroptosis in human ovarian cancer cells

Authors: Xue-lian Zheng1, Jiao-jiao Yang2, Yan-yun Wang1, Qin Li1, Ya-ping Song1, Min Su1, Jin-ke Li1, Lin Zhang1, Zhi-ping Li2, Bin Zhou1, Yong Lin3
1 Laboratory of Molecular and Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University) of Ministry of Education, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
2 Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
3 Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive, SE, Albuquerque, NM 87108, USA
Correspondence to: Bin Zhou: zb630@163.com, Yong Lin: ylin@lrri.org,
DOI: 10.1038/s41401-019-0340-7
Received: 9 July 2019
Accepted: 26 November 2019
Advance online: 2 April 2020

Abstract

Receptor-interacting protein 1 (RIP1, also known as RIPK1) is not only a tumor-promoting factor in several cancers but also mediates either apoptosis or necroptosis in certain circumstances. In this study we investigated what role RIP1 plays in human ovarian cancer cells. We showed that knockout (KO) of RIP1 substantially suppressed cell proliferation, accompanied by the G2/M checkpoint arrest in two human ovarian cancer cell lines SKOV3 and A2780. On the other hand, RIP1 KO remarkably attenuated cisplatin-induced cytotoxicity, which was associated with reduction of the apoptosis markers PARP cleavage and the necroptosis marker phospho- MLKL. We found that RIP1 KO suppressed cisplatin-induced ROS accumulation in both SKOV3 and A2780 cells. ROS scavenger BHA, apoptosis inhibitor Z-VAD or necroptosis inhibitor NSA could effectively suppress cisplatin’s cytotoxicity in the control cells, suggesting that ROS-mediated apoptosis and necroptosis were involved in cisplatin-induced cell death. In addition, blocking necroptosis with MLKL siRNA effectively attenuated cisplatin-induced cytotoxicity. In human ovarian cancer A2780 cell line xenograft nude mice, RIP1 KO not only significantly suppressed the tumor growth but also greatly attenuated cisplatin’s anticancer activity. Our results demonstrate a dual role of RIP1 in human ovarian cancer: it acts as either a tumor-promoting factor to promote cancer cell proliferation or a tumor-suppressing factor to facilitate anticancer effects of chemotherapeutics such as cisplatin.
Keywords: RIP1; RIPK1; ovarian cancer; cisplatin; taxol; ROS; apoptosis; necroptosis; proliferation; BHA; Z-VAD; NSA

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