1,25-Dihydroxyvitamin D ₃ enhances NK susceptibility of human melanoma cells via Hsp60-mediated FAS expression

The active metabolite of vitamin D ₃, 1α,25(OH) ₂D ₃, displays anticancer effects by regulating cell cycle and apoptosis in many cancer cells. However, it has not been determined whether 1α,25(OH) ₂D ₃ increases the susceptibility of cancer cells to NK cells. Here, we investigated the anticancer effect of 1α,25(OH) ₂D ₃ in human melanoma cell lines by investigating enhancement of NK susceptibility and elucidating the mediator of NK cytotoxicity. 1α,25(OH) ₂D ₃-resistant melanoma cells (G-361 and SK-MEL-5) treated with 1α,25(OH) ₂D ₃ showed higher susceptibility to NK cells with up-regulation of Fas expression. Furthermore, G-361 cells treated with 1α,25(OH) ₂D ₃ showed significantly increased caspase activity. In addition to Fas up-regulation, expression of heat shock protein 60 (Hsp60) was elevated by 1α,25(OH) ₂D ₃. Increased expression of Hsp60 by 1α,25(OH) ₂D ₃ was related to not only up-regulation of Fas expression but also to NK susceptibility of G-361 cells. Taken together, our data suggest that 1α,25(OH) ₂D ₃ acts as an anticancer agent by increasing expression of Fas on the surface of melanoma cells through Hsp60 induction and strengthens caspase sensitivity to Fas-mediated apoptotic pathway by NK cells. 1α,25(OH) ₂D ₃ treatment may therefore have a preventive role in melanoma occurrence or potentiate the anticancer effects of NK-cell immune therapy.