Molecular regulation of prostate biology and prostate cancer by signaling through the vitamin D receptor.

摘要

High vitamin D status (serum 25-hydroxyvitamin D) and UV light exposure are associated with reduced risk of prostate cancer. The biologically active form of vitamin D, 1 alpha, 25-dihydroxyvitamin D (1,25(OH)2D) regulates expression of its target genes via its ligand activated transcription factor, the vitamin D receptor (VDR). To clarify the role of VDR signaling in the prevention of prostate cancer, we conducted three experiments. In the first experiment we used androgen depletion/repletion model in mice to test whether prostate epithelial cell (PEC) VDR level was important for the control of PEC proliferation and apoptosis. Analysis of the data revealed that loss of VDR signaling in mouse PEC increased proliferation by 97% (p0.05) and reduced apoptosis by 44% (p0.05) after androgen depletion and repletion. PEC VDR deletion also had a growth inhibitory effect on stromal cells during phases of active growth indicating a possible role of cell-cell communication in the regulation of prostate biology. In the second experiment we used APT121 mouse model of prostate cancer to test whether PEC VDR level was important for the control of prostate cancer. The data revealed that PEC VDR deletion increased the incidence of advanced lesions (i.e. adenocarcinomas) and reduced the incidence of less-advanced preneoplastic lesions in anterior prostate lobe. The number of foci and the area affected by adenocarcinoma was also significantly greater in animals with VDR knockout. These data suggest that increased progression of carcinogenesis occurs in the absence of VDR signaling in PEC. In the final experiment we used microarray analysis to identify potential vitamin D target genes and pathways affected by 1,25(OH)2D. Immortalized but non-tumorigenic prostate epithelial cells, (RWPE1), were treated with 1,25(OH)2D or vehicle for 6, 24, or 48 h and the transcript profile was assessed. Many transcript level changes were observed at each time point at a 5% false detection rate. Over 260 transcripts were regulated by 1,25(OH) 2D at all time points (79% up) and are considered potential direct vitamin D target genes that may modulate prostate carcinogenesis. Several of these were identified as direct targets of 1,25(OH)2D by using ChIP assay. Functional analysis of the microarray data revealed modulation of several functionally distinct pathways by 1,25(OH)2D, i.e. suppression of pro-proliferative and WNT signaling, suppression of pro-angiogenic VEGF signaling, suppression of pro-inflammatory cytokine signaling pathways, up-regulation of transcripts involved in the protection of cells from oxidative stress or DNA damage. This data demonstrated that VDR signaling is critical for anticancer effects of vitamin D. 1,25(OH)2D can suppress growth of normal prostate epithelial cells via multiple mechanism and initiate mechanisms preventing carcinogenic changes.