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.
The secosteroid hormone 1alpha, 25-dihydroxyvitamin D3 (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-beta superfamily and has been implicated in a variety of functions directly related totumorigenicity 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.
Lambert
James R
JR
Department of Pathology, University of Colorado Health Sciences Center, Aurora, Colorado 80045, USA. jim.lambert@uchsc.edu
Kelly
Julie A
JA
Shim
Minsub
M
Huffer
William E
WE
Nordeen
Steven K
SK
Baek
Seung Joon
SJ
Eling
Thomas E
TE
Lucia
M Scott
MS
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002117:Calcitriol / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055436:Growth Differentiation Factor 15; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D011923:Rats, Nude; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; C526140:GDF15 protein, human; C526142:Gdf15 protein, rat; D055436:Growth Differentiation Factor 15; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D002117:Calcitriol