High basal NF-κB activity in nonpigmented melanoma cells is associated with an enhanced sensitivity to vitamin D3 derivatives.

Abstract

BACKGROUND:

Melanoma is highly resistant to current modalities of therapy, with the extent of pigmentation playing an important role in therapeutic resistance. Nuclear factor-κB (NF-κB) is constitutively activated in melanoma and can serve as a molecular target for cancer therapy and steroid/secosteroid action.

METHODS:

Cultured melanoma cells were used for mechanistic studies on NF-κB activity, utilising immunofluorescence, western blotting, EMSA, ELISA, gene reporter, and estimated DNA synthesis assays. Formalin-fixed, paraffin-embedded specimens from melanoma patients were used for immunocytochemical analysis of NF-κB activity in situ.

RESULTS:

Novel 20-hydroxyvitamin (20(OH)D(3)) and classical 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) secosteroids inhibited melanoma cell proliferation. Active forms of vitamin D were found to inhibit NF-κB activity in nonpigmented cells, while having no effect on pigmented cells. Treatment of nonpigmented cells with vitamin D3 derivatives inhibited NF-κB DNA binding and NF-κB-dependent reporter assays, as well as inhibited the nuclear translocation of the p65 NF-κB subunit and its accumulation in the cytoplasm. Moreover, analysis of biopsies of melanoma patients showed that nonpigmented and slightly pigmented melanomas displayed higher nuclear NF-κB p65 expression than highly pigmented melanomas.

CONCLUSION:

Classical 1,25(OH)(2)D(3) and novel 20(OH)D(3) hydroxyderivatives of vitamin D3 can target NF-κB and regulate melanoma progression in nonpigmented melanoma cells. Melanin pigmentation is associated with the resistance of melanomas to 20(OH)D(3) and 1,25(OH)(2)D(3) treatment.

• Authors: Z Janjetovic, A A Brozyna, R C Tuckey, T-K Kim, M N Nguyen, W Jozwicki, S R Pfeffer, L M Pfeffer, A T Slominski
• Journal: British journal of cancer (Br J Cancer) Vol. 105 Issue 12 Pg. 1874-84 (Dec 06 2011) ISSN: 1532-1827 [Electronic] England
• PMID: 22095230 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Cholecalciferol

Topics

• Cell Division (drug effects)
• Cell Line, Tumor
• Cholecalciferol (pharmacology)
• Humans
• Melanoma (metabolism, pathology)
• NF-kappa B (metabolism)