Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt/β-catenin signaling

查看全文 作　　者：Yu [1]Zheng;Trupti [1]Trivedi;Ruby CY [2,3]Lin;Colette Fong-[1]Yee;Rick [1]Nolte;Jeline [1]Manibo;Yunzhao [1,4]Chen;Musharraf [4]Hossain;Konstantin [1]Horas;Colin [5]Dunstan;Hong [1,6]Zhou;Markus J [1,6]Seibel

机构地区：[1]Bone Research Program, ANZAC Research Institute;[2]Asbestos Diseases Research Institute, Cardiothoracic Genomics;[3]School of Medical Sciences, University of New South Wales;[4]Department of Pathology, Shihezi University School of Medicine;[5]Biomedical Engineering, AMME, University of Sydney;[6]Concord Clinical School, The University of Sydney

出　　处：《Bone Research》索引2017年第5卷第3期,共12页

基　　金：supported by Cancer Institute NSW CDF fellowship (YZ);Cure Cancer Foundation of Australia (YZ);Cancer Council New South Wales (MJS, YZ, HZ, and CRD);Prostate Cancer Foundation of Australia (MJS, YZ, HZ, and CRD);NH and MRC Early Career Fellowship 596870 (YZ);German Research Foundation HO 5109/2-1 and HO 5109/2-2 (KH) 摘　　要：Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D,1,25-dihydroxy-vitamin D [1,25(OH)2 D] are mediated through binding to the vitamin D receptor(VDR). Here,we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad(MDA-MB-231),subcutaneously(PC3) or intra-tibially(both cell lines) in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls.These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/β-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1,interleukin-6(IL-6), and IL-8. Stabilization of β-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer. 关键词：β-catenin 维生素D受体 Wnt信号通路细胞凋亡前列腺癌乳腺癌诱导白细胞介素-6

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Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt/β-catenin signaling

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