Vitamin D-induced up-regulation of tumour necrosis factor alpha (TNF-α) in prostate cancer cells

1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3 or calcitriol) is an active hormone that regulates cellular proliferation and induces apoptosis in cancer cells. Here we report on a new calcitriol target gene in prostate cancer cells, tumour necrosis factor α (TNF-α). Calcitriol and its analogue CB1093 up-regulate TNF-α mRNA expression in LNCaP and PC-3 cells. The stimulation is dose-dependent in both of these cell lines, demonstrated by the quantitative real-time polymerase chain reaction. Calcitriol and CB1093 act synergistically with human recombinant TNF-α in activation of TNF-α mRNA expression in LNCaP but not in PC-3 cells. Transcriptional activation of TNF-α gene by calcitriol or CB1093 does not lead to TNF-α protein secretion, however calcitriol and CB1093 enhance TPA-stimulated TNF-α production in LNCaP cells. We did not observe any significant effect of calcitriol on regulation of TNFR1 at the level of gene expression. Nor does calcitriol affect transcriptional regulation of cytokine (IL-1, IL-6) and cytokine receptor genes in LNCaP and PC-3 prostate cancer cell lines. Calcitriol and its analogue CB1093 at 10 nM concentration induce programmed cell death in LNCaP cells. Combined addition of human recombinant TNF-α with calcitriol or CB1093 cause enhanced effect in induction of apoptosis. We conclude that under physiological conditions vitamin D activates only the transcription of TNF-α gene, for TNF-α protein synthesis additional cofactors are required. Therefore a cooperation of vitamin D and TNF-α may play an important role in the control of cell growth in prostate cancer.