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

Z. Janjetovic, A. A. Brozyna, R. C. Tuckey, T. K. Kim, M. N. Nguyen, W. Jozwicki, S. R. Pfeffer, Lawrence Pfeffer, A. T. Slominski

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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-B (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-B 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-B 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-B activity in nonpigmented cells, while having no effect on pigmented cells. Treatment of nonpigmented cells with vitamin D3 derivatives inhibited NF-B DNA binding and NF-B-dependent reporter assays, as well as inhibited the nuclear translocation of the p65 NF-B 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-B p65 expression than highly pigmented melanomas. Conclusion: Classical 1,25(OH) 2D 3 and novel 20(OH)D 3 hydroxyderivatives of vitamin D 3 can target NF-B 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) 2D 3 treatment.

Original languageEnglish (US)
Pages (from-to)1874-1884
Number of pages11
JournalBritish Journal of Cancer
Volume105
Issue number12
DOIs
StatePublished - Dec 6 2011

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Cholecalciferol
Melanoma
Secosteroids
Pigmentation
Therapeutics
DNA
Melanins
Reporter Genes
Vitamin D
Paraffin
Formaldehyde
Fluorescent Antibody Technique
Cultured Cells
Cytoplasm
Western Blotting
Enzyme-Linked Immunosorbent Assay
Steroids
Cell Proliferation
Biopsy

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Janjetovic, Z., Brozyna, A. A., Tuckey, R. C., Kim, T. K., Nguyen, M. N., Jozwicki, W., ... Slominski, A. T. (2011). High basal NF-κB activity in nonpigmented melanoma cells is associated with an enhanced sensitivity to vitamin D3 derivatives. British Journal of Cancer, 105(12), 1874-1884. https://doi.org/10.1038/bjc.2011.458

High basal NF-κB activity in nonpigmented melanoma cells is associated with an enhanced sensitivity to vitamin D3 derivatives. / Janjetovic, Z.; Brozyna, A. A.; Tuckey, R. C.; Kim, T. K.; Nguyen, M. N.; Jozwicki, W.; Pfeffer, S. R.; Pfeffer, Lawrence; Slominski, A. T.

In: British Journal of Cancer, Vol. 105, No. 12, 06.12.2011, p. 1874-1884.

Research output: Contribution to journalArticle

Janjetovic, Z, Brozyna, AA, Tuckey, RC, Kim, TK, Nguyen, MN, Jozwicki, W, Pfeffer, SR, Pfeffer, L & Slominski, AT 2011, 'High basal NF-κB activity in nonpigmented melanoma cells is associated with an enhanced sensitivity to vitamin D3 derivatives', British Journal of Cancer, vol. 105, no. 12, pp. 1874-1884. https://doi.org/10.1038/bjc.2011.458
Janjetovic, Z. ; Brozyna, A. A. ; Tuckey, R. C. ; Kim, T. K. ; Nguyen, M. N. ; Jozwicki, W. ; Pfeffer, S. R. ; Pfeffer, Lawrence ; Slominski, A. T. / High basal NF-κB activity in nonpigmented melanoma cells is associated with an enhanced sensitivity to vitamin D3 derivatives. In: British Journal of Cancer. 2011 ; Vol. 105, No. 12. pp. 1874-1884.
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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-B (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-B 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-B 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-B activity in nonpigmented cells, while having no effect on pigmented cells. Treatment of nonpigmented cells with vitamin D3 derivatives inhibited NF-B DNA binding and NF-B-dependent reporter assays, as well as inhibited the nuclear translocation of the p65 NF-B 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-B p65 expression than highly pigmented melanomas. Conclusion: Classical 1,25(OH) 2D 3 and novel 20(OH)D 3 hydroxyderivatives of vitamin D 3 can target NF-B 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) 2D 3 treatment.",
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AU - Brozyna, A. A.

AU - Tuckey, R. C.

AU - Kim, T. K.

AU - Nguyen, M. N.

AU - Jozwicki, W.

AU - Pfeffer, S. R.

AU - Pfeffer, Lawrence

AU - Slominski, A. T.

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N2 - Background: Melanoma is highly resistant to current modalities of therapy, with the extent of pigmentation playing an important role in therapeutic resistance. Nuclear factor-B (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-B 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-B 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-B activity in nonpigmented cells, while having no effect on pigmented cells. Treatment of nonpigmented cells with vitamin D3 derivatives inhibited NF-B DNA binding and NF-B-dependent reporter assays, as well as inhibited the nuclear translocation of the p65 NF-B 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-B p65 expression than highly pigmented melanomas. Conclusion: Classical 1,25(OH) 2D 3 and novel 20(OH)D 3 hydroxyderivatives of vitamin D 3 can target NF-B 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) 2D 3 treatment.

AB - Background: Melanoma is highly resistant to current modalities of therapy, with the extent of pigmentation playing an important role in therapeutic resistance. Nuclear factor-B (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-B 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-B 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-B activity in nonpigmented cells, while having no effect on pigmented cells. Treatment of nonpigmented cells with vitamin D3 derivatives inhibited NF-B DNA binding and NF-B-dependent reporter assays, as well as inhibited the nuclear translocation of the p65 NF-B 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-B p65 expression than highly pigmented melanomas. Conclusion: Classical 1,25(OH) 2D 3 and novel 20(OH)D 3 hydroxyderivatives of vitamin D 3 can target NF-B 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) 2D 3 treatment.

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