Abstract
BackgroundProstate cancer is the second leading cause of cancer mortality among US men. Epidemiological evidence suggests that high vitamin D status protects men from prostate cancer and the active form of vitamin D, 1α,25 dihydroxyvitamin D3 (1,25(OH)2D) has anti-cancer effects in cultured prostate cells. Still, the molecular mechanisms and the gene targets for vitamin D-mediated prostate cancer prevention are unknown.ResultsWe examined the effect of 1,25(OH)2D (+/- 100 nM, 6, 24, 48 h) on the transcript profile of proliferating RWPE1 cells, an immortalized, non-tumorigenic prostate epithelial cell line that is growth arrested by 1,25(OH)2D (Affymetrix U133 Plus 2.0, n = 4/treatment per time and dose). Our analysis revealed many transcript level changes at a 5% false detection rate: 6 h, 1571 (61% up), 24 h, 1816 (60% up), 48 h, 3566 (38% up). 288 transcripts were regulated similarly at all time points (182 up, 80 down) and many of the promoters for these transcripts contained putative vitamin D response elements. Functional analysis by pathway or Gene Set Analysis revealed early suppression of WNT, Notch, NF-kB, and IGF1 signaling. Transcripts related to inflammation were suppressed at 6 h (e.g. IL-1 pathway) and suppression of proinflammatory pathways continued at later time points (e.g. IL-17 and IL-6 pathways). There was also evidence for induction of anti-angiogenic pathways and induction of transcripts for protection from oxidative stress or maintenance of cell redox homeostasis at 6 h.ConclusionsOur data reveal of large number of potential new, direct vitamin D target genes relevant to prostate cancer prevention. In addition, our data suggests that rather than having a single strong regulatory effect, vitamin D orchestrates a pattern of changes within prostate epithelial cells that limit or slow carcinogenesis.
Highlights
Prostate cancer is the second leading cause of cancer mortality among US men
At 6 and 24 h, the transcripts were predominantly up-regulated (60.7% and 59.6%) while at the 48 h time point the transcripts were predominantly down-regulated (62.3%). 1,25 (OH)2D treatment significantly altered the expression of 288 transcripts at all three time points; 262 of these changed in the same direction and 63.2% were up-regulated
By applying microarray technology to the immortalized but non-tumorigenic human prostate epithelial cell line RWPE1, we have identified a number of mechanisms by which vitamin D may influence the early stages of prostate carcinogenesis
Summary
Epidemiological evidence suggests that high vitamin D status protects men from prostate cancer and the active form of vitamin D, 1a,25 dihydroxyvitamin D3 (1,25(OH)2D) has anti-cancer effects in cultured prostate cells. The growth inhibitory actions of 1,25(OH)2D require the presence of the vitamin D receptor (VDR), a ligandinducible transcription factor [5,6,7]. It is not clear whether the chemopreventative effect of high vitamin D status in the normal, healthy prostate is mediated by the same mechanisms.
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