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

doi:10.7150/jca.47111

	Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma
	Zhu, Guanxia 2; Li, Xia 1; Li, Jiong 3; Zhou, Wei 4; Chen, Zhongjian 1; Fan, Yun 1; Jiang, Youhua 1; Zhao, Yue 1; Sun, Guogui 5; Mao, Weimin 2
刊名	JOURNAL OF CANCER
	2020
卷号	11
关键词	esophageal squamous cell carcinoma oral squamous cell carcinoma arsenic trioxide cyclin D1 PD-L1 CDK4/6
ISSN号	1837-9664
DOI	10.7150/jca.47111
通讯作者	Zhao, Yue(zhaoyue@zjcc.org.cn) ; Sun, Guogui(guogui_sun2013@163.com) ; Mao, Weimin(weimin.mao@zjcc.org.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[81802472] ; Zhejiang Province Public Welfare Technology Application Research Project[LGJ18H310001]
WOS关键词	OPEN-LABEL ; CANCER ; THERAPY ; PROTEOLYSIS ; RESISTANCE ; APOPTOSIS ; ARREST ; GENES ; PD-L1
WOS研究方向	Oncology
语种	英语
出版者	IVYSPRING INT PUBL
WOS记录号	WOS:000575099000006
资助机构	National Natural Science Foundation of China ; Zhejiang Province Public Welfare Technology Application Research Project
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/104350]
专题	中国科学院合肥物质科学研究院
通讯作者	Zhao, Yue; Sun, Guogui; Mao, Weimin
作者单位	1.Chinese Acad Sci, Zhejiang Canc Hosp, Univ Chinese Acad Sci, Inst Canc & Basic Med,Canc Hosp, Hangzhou 310022, Peoples R China 2.Wenzhou Med Univ, Wenzhou 325035, Peoples R China 3.Virginia Commonwealth Univ, Massey Canc Ctr, Philips Inst Oral Hlth Res, Dept Med Chem, Richmond, VA 23298 USA 4.Chinese Acad Med Sci & Peking Union Med Coll, State Key Lab Mol Oncol, Natl Canc Ctr, Natl Clin Res Ctr Canc,Canc Hosp, Beijing 100021, Peoples R China 5.North China Univ Sci & Technol, Affiliated Peoples Hosp, Sch Publ Hlth, Tangshan 063001, Peoples R China
推荐引用方式 GB/T 7714	Zhu, Guanxia,Li, Xia,Li, Jiong,et al. Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma[J]. JOURNAL OF CANCER,2020,11.
APA	Zhu, Guanxia.,Li, Xia.,Li, Jiong.,Zhou, Wei.,Chen, Zhongjian.,...&Mao, Weimin.(2020).Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma.JOURNAL OF CANCER,11.
MLA	Zhu, Guanxia,et al."Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma".JOURNAL OF CANCER 11(2020).