J Cancer 2020; 11(22):6516-6529. doi:10.7150/jca.47111 This issue

Research Paper

Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma

Guanxia Zhu2, Xia Li1, Jiong Li3, Wei Zhou4, Zhongjian Chen1, Yun Fan1, Youhua Jiang1, Yue Zhao1✉, Guogui Sun5✉, Weimin Mao2✉

1. Cancer Hospital of University of Chinese Academy of Sciences, Institute of Cancer and Basic Medicine of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
2. Wenzhou Medical University, Wenzhou, 325035, China.
3. Department of Medicinal Chemistry, Massey Cancer Center, Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia 23298-0540, United States.
4. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
5. North China University of Science and Technology Affiliated People's Hospital, School of Public Health, North China University of Science and Technology, Tangshan, 063001, China.

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Zhu G, Li X, Li J, Zhou W, Chen Z, Fan Y, Jiang Y, Zhao Y, Sun G, Mao W. Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma. J Cancer 2020; 11(22):6516-6529. doi:10.7150/jca.47111. Available from https://www.jcancer.org/v11p6516.htm

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Arsenic trioxide (ATO) is widely studied for its antitumor efficacy and several recent studies suggested the immune modulatory effects of ATO in animal models. In this study we found ATO treatment induced increased ROS production and DNA damage in esophageal squamous cell carcinoma (ESCC) cells, led to DNA damage mediated degradation of Cyclin D1 and upregulation of PD-L1 in these cancer cells. Mechanistically, we found ATO induced a transient upregulation and nuclear translocation of Cyclin D1 by sumoylation. Followed with increased ubiquitination and degradation of Cyclin D1 through T286 phosphorylation, and at least partly mediated by Stat1 Y701 phosphorylation. We observed inversed correlations between Cyclin D1 and PD-L1 expression levels in human ESCC tissues. With 4NQO induced PD-L1 humanized mouse oral and esophageal squamous carcinoma model, we found combinatory administration of ATO and check point inhibitor resulted in a significant reduction of tumor volumes. Inversed correlation between Cyclin D1 with PD-L1 was also observed in the 4NQO induced mouse ESCC and OSCC model. Together, these data suggested ATO induced degradation of Cyclin D1 and functional suppression of CDK4/6 pathway sensitized OSCC and ESCC to checkpoint inhibitor treatment.

Keywords: esophageal squamous cell carcinoma, oral squamous cell carcinoma, arsenic trioxide, cyclin D1, PD-L1, CDK4/6