The active metabolite of
vitamin D(3), 1α,25(
OH)(2)D(3) , displays anticancer effects by regulating cell cycle and apoptosis in many
cancer cells. However, it has not been determined whether 1α,25(
OH)(2)D(3) increases the susceptibility of
cancer cells to NK cells. Here, we investigated the anticancer effect of 1α,25(
OH)(2)D(3) in human
melanoma cell lines by investigating enhancement of NK susceptibility and elucidating the mediator of NK cytotoxicity. 1α,25(OH)(2)D(3)-resistant
melanoma cells (G-361 and SK-MEL-5) treated with 1α,25(
OH)(2)D(3) showed higher susceptibility to NK cells with up-regulation of Fas expression. Furthermore, G-361 cells treated with 1α,25(
OH)(2)D(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)(2) D(3) . Increased expression of Hsp60 by 1α,25(
OH)(2)D(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)(2)D(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)(2)D(3) treatment may therefore have a preventive role in
melanoma occurrence or potentiate the anticancer effects of NK-cell immune
therapy.