Carbidopa suppresses prostate cancer via aryl hydrocarbon receptor-mediated ubiquitination and degradation of androgen receptor

doi:10.1038/s41389-020-0236-x

科研成果详情

题名	Carbidopa suppresses prostate cancer via aryl hydrocarbon receptor-mediated ubiquitination and degradation of androgen receptor
作者	Chen, Zhiwei1,2; Cai, Aimin 1; Zheng, Hailun1; Huang, Huirong1; Sun, Rui1; Cui, Xiao 1; Ye, Weijian 1,2; Yao, Qing2,3; Chen, Ruijie1,2; Kou, Longfa1,2
发表日期	2020-05-13
发表期刊	ONCOGENESIS 影响因子和分区
语种	英语
原始文献类型	Article
其他关键词	L-DOPA ; CELLS ; EXPRESSION ; THERAPY ; PROTEIN ; TARGET
摘要	Carbidopa, a peripheral decarboxylase inhibitor used with L-DOPA to treat Parkinson's disease, has attracted significant interest in recent years for its anticancer effect. Increasing evidence reveals that Carbidopa can inhibit cancer cell growth and induce apoptosis through aryl hydrocarbon receptor (AHR) in some cancers. However, the antitumor effect of Carbidopa in prostate cancer (PCa) is not fully understood. Androgen receptor (AR) plays a central role in PCa, even in advanced castrate-resistant disease. In the present study, we report that Carbidopa suppresses the growth of PCa by downregulating the protein expression of AR. Carbidopa inhibits proliferation and migration of LNCaP cells and promotes apoptosis, but has no effect on the AR-independent prostate cell line DU145. Carbidopa increases ubiquitination of AR in LNCaP cells. Several studies have shown that AHR can act as an E3 ubiquitin ligase and promote the proteasomal degradation of AR. Quantitative RT-PCR, immunofluorescence staining and immunoblotting assay demonstrate that AHR is induced and activated by Carbidopa, and the co-immunoprecipitation assay shows that AR interacts with AHR, firmly confirming that Carbidopa decreases AR protein level though AHR-induced proteasomal degradation. In addition, Carbidopa suppresses PCa growth in vivo when xenografted into immunocompromised mice. Carbidopa treatment increases AHR protein level and decreases AR protein level in tumor tissues. Taken together, our study implicates Carbidopa for the first time in effective suppression of prostate cancer via a mechanism, involving AHR-mediated proteasomal degradation of AR.
资助项目	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81803443, 81903551]; Zhejiang Pharmaceutical Association [2018ZYY44, 2018ZYY15, 2019ZYY39]; Natural Science Foundation of Zhejiang ProvinceNatural Science Foundation of Zhejiang Province [LQ19H300001]; Wenzhou Science and Technology Bureau [Y20180180, Y20180208, Y20190174, Y20190177, ZY2019007]; Special Project for Significant New Drug Research and Development in the Major National Science and Technology Projects of China [2020ZX09201002]
出版者	NATURE PUBLISHING GROUP
出版地	NEW YORK
ISSN	2157-9024
卷号	9 期号:5 页码:49
DOI	10.1038/s41389-020-0236-x
页数	13
WOS类目	Oncology
WOS研究方向	Oncology
WOS记录号	WOS:000536491000001
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	32404918
PMC记录号	PMC7220950
SCOPUSEID	2-s2.0-85084637431
通讯作者地址	[Chen, Ruijie]Department of Pharmacy,The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University,Wenzhou,325027,China
Scopus学科分类	Molecular Biology;Cancer Research
引用统计	被引频次：5[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/15090
专题	第二临床医学院、附属第二医院、育英儿童医院附属第二医院药学院（分析测试中心）_药学系
通讯作者	Chen, Ruijie
作者单位	1.Department of Pharmacy,The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University,Wenzhou,325027,China; 2.Wenzhou Municipal Key Laboratory of Paediatric Pharmacy,Wenzhou,325027,China; 3.Department of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,325035,China
第一作者单位	第二临床医学院，附属第二医院、育英儿童医院; 附属第二医院
通讯作者单位	第二临床医学院，附属第二医院、育英儿童医院; 附属第二医院
第一作者的第一单位	第二临床医学院，附属第二医院、育英儿童医院
推荐引用方式 GB/T 7714	Chen, Zhiwei,Cai, Aimin,Zheng, Hailun,et al. Carbidopa suppresses prostate cancer via aryl hydrocarbon receptor-mediated ubiquitination and degradation of androgen receptor[J]. ONCOGENESIS,2020,9(5):49.
APA	Chen, Zhiwei., Cai, Aimin., Zheng, Hailun., Huang, Huirong., Sun, Rui., ... & Kou, Longfa. (2020). Carbidopa suppresses prostate cancer via aryl hydrocarbon receptor-mediated ubiquitination and degradation of androgen receptor. ONCOGENESIS, 9(5), 49.
MLA	Chen, Zhiwei,et al."Carbidopa suppresses prostate cancer via aryl hydrocarbon receptor-mediated ubiquitination and degradation of androgen receptor".ONCOGENESIS 9.5(2020):49.