1,25-Dihydroxyvitamin D₃ enhances NK susceptibility of human melanoma cells via Hsp60-mediated FAS expression

Eur J Immunol. 2011 Oct;41(10):2937-46. doi: 10.1002/eji.201141597. Epub 2011 Sep 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / immunology
  • Blotting, Western
  • Calcitriol / pharmacology*
  • Caspase 3 / metabolism
  • Caspase 8 / metabolism
  • Cell Line, Tumor
  • Chaperonin 60 / metabolism*
  • Fas Ligand Protein / metabolism
  • Flow Cytometry
  • Humans
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism*
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Melanoma / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • fas Receptor / metabolism*


  • Chaperonin 60
  • Fas Ligand Protein
  • RNA, Small Interfering
  • fas Receptor
  • Caspase 3
  • Caspase 8
  • Calcitriol