Abstract
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)2D] 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.
Highlights
Breast and prostate cancers are among the most prevalent malignancies in industrialized countries
To assess vitamin D receptor (VDR) ablation on a functional basis, MDA-VDR-KD and MDA-NT cells 24 h post plating were treated for 8 h with 10− 8 mol · L−1 1,25(OH)2D3 in media supplemented with 2% charcoal stripped heatinactivated fetal bovine serum and the expression of CYP24, a downstream target gene of the classical VDR signaling pathway, was measured
VDR knockdown in MDA-MB-231 cells reduces cell proliferation and increases cell apoptosis: in vitro studies As 1,25(OH)2D3 treatment suppresses cancer cell growth in vitro, and vitamin D deficiency enhances breast and prostate cancer growth in animal models of bone metastasis,[8,10,13] we hypothesized that ablation of the VDR in human breast cancer cells would promote tumor growth
Summary
Breast and prostate cancers are among the most prevalent malignancies in industrialized countries. Mortality has steadily declined over the past 20 years, a significant proportion of patients eventually develop metastatic disease, most frequently to the skeleton.[1] Skeletal related events due to bone metastasis are frequent and a major cause of mortality and morbidity.[2,3]. Inhibition of bone remodeling with potent anti-resorptive treatments (for example, osteoprotegerin, zoledronic acid) fails to completely reverse the pro-proliferative effects of vitamin D deficiency,[8,10] suggesting that vitamin D deficiency may promote cancer cell growth by an additional and possibly direct mechanism
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