Molecular Mechanism for Prostate Cancer Resistance to the Anti-tumor Activity of Vitamin D

摘要

The original purpose of this research, as proposed in the statement of work, was to determine the mechanism by which prostate cancer (PCa) cells become resistant to the anti-tumor activity of vitamin D. The proposal focused on a PCa-specific deficiency in a key vitamin D metabolizing enzyme, 1alpha- hydroxylase (1alphaOH). During the first year, we encountered unforeseen difficulties with one of the key techniques in the original proposal. Therefore we decided to focus on vitamin D target genes, whose expression would be effected downstream of 1alphaOH bioactivation of vitamin D. Using normal human prostatic epithelial cells and prostate cancer cell lines, we examined the role of map kinase phosphatase 5 (MKP5), a recently discovered target gene of vitamin D, in mediating anti-tumor activities. MKP5 dephosphorylates/inactivates the stress activated protein kinase p38. Interestingly, in the prostate cancer cell lines LNCaP, PC-3 and DU 145, 1,25D did not up-regulate MKP5 or inactivate p38. 1,25D inhibited both UV and inflammation-induced p38 phosphorylation and downstream IL-6 production in a MKP5-dependendt manner. As inflammation emerges as a risk factor for prostate cancer, there is potential for chemoprevention by anti-inflammatory agents. We proceeded to expand upon these results and focused on MKP5 as a mediator of potentially chemopreventive anti-inflammatory activities of other phytochemicals in the prostate. Curcumin, the phytochemical found in turmeric, up-regulated MKP5, subsequently decreasing cytokine-induced p38-dependent pro- inflammatory changes in normal prostatic epithelial cells.