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

Abstract

The active metabolite of vitamin D-3, 1 alpha,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 1 alpha,25(OH)(2)D-3 increases the susceptibility of cancer cells to NK cells. Here, we investigated the anticancer effect of 1 alpha,25(OH)(2)D-3 in human melanoma cell lines by investigating enhancement of NK susceptibility and elucidating the mediator of NK cytotoxicity. 1 alpha,25(OH)(2)D-3-resistant melanoma cells (G-361 and SK-MEL-5) treated with 1 alpha,25(OH)(2)D-3 showed higher susceptibility to NK cells with up-regulation of Fas expression. Furthermore, G-361 cells treated with 1 alpha,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 1 alpha,25(OH)(2)D-3. Increased expression of Hsp60 by 1 alpha,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 1 alpha,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. 1 alpha,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.