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Prostate derived factor in human prostate cancer cells: Gene induction by vitamin D via a p53‐dependent mechanism and inhibition of prostate cancer cell growth
Author(s) -
Lambert James R.,
Kelly Julie A.,
Shim Minsub,
Huffer William E.,
Nordeen Steven K.,
Baek Seung Joon,
Eling Thomas E.,
Lucia M. Scott
Publication year - 2006
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.20692
Subject(s) - calcitriol receptor , lncap , prostate cancer , cancer research , biology , cell growth , cancer cell , growth factor , transfection , cancer , cell culture , vitamin d and neurology , receptor , endocrinology , genetics
Abstract The secosteroid hormone 1α, 25‐dihydroxyvitamin D 3 (1,25D) has been shown to regulate the growth and differentiation of human prostate cancer (PCa) cells, although the precise molecular mechanisms mediating these effects have not been defined. Previous studies in our laboratory demonstrated that the antiproliferative effects of 1,25D on PCa cells are mediated through the nuclear vitamin D receptor (VDR). In the present study, we performed gene profiling of LNCaP human PCa cells following 1,25D treatment and identified the antitumorigenic gene, prostate derived factor (PDF), as being highly induced by 1,25D. PDF is a member of the TGF‐β superfamily and has been implicated in a variety of functions directly related to tumorigenicity including antiproliferative and pro‐apoptotic effects. Gene expression studies using 1,25D analogs and a VDR antagonist demonstrate that 1,25D‐mediated induction of PDF message and protein in PCa cells is dependent on VDR action. PDF is a transcriptional target of the tumor suppressor, p53. Here we show that the expression of PDF in nine PCa cell lines is dependent on functional p53. Additionally, transfection of p53‐null ALVA‐31 PCa cells with a p53 expression plasmid, and expression of dominant negative p53 in LNCaP PCa cells, show that the ability of VDR to induce PDF requires functional p53. Importantly, forced PDF expression in PC‐3 cells results in decreased cell proliferation, soft agar cloning, and xenograft tumor size. These data demonstrate that PDF exerts antitumorigenic properties on PCa cells and its regulation by 1,25D may provide insights into the action of 1,25D in PCa. J. Cell. Physiol. 208: 566–574, 2006. © 2006 Wiley‐Liss, Inc.