title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Pathology and Laboratory Medicine, Center for Cancer Research, University of Tennessee Health Science Center, 930 Madison Avenue, Memphis, TN 38163, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Janjetovic
authors.forename: A A
authors.initials: AA
authors.lastname: Brozyna
authors.forename: R C
authors.initials: RC
authors.lastname: Tuckey
authors.forename: T-K
authors.initials: TK
authors.lastname: Kim
authors.forename: M N
authors.initials: MN
authors.lastname: Nguyen
authors.forename: W
authors.initials: W
authors.lastname: Jozwicki
authors.forename: S R
authors.initials: SR
authors.lastname: Pfeffer
authors.forename: L M
authors.initials: LM
authors.lastname: Pfeffer
authors.forename: A T
authors.initials: AT
authors.lastname: Slominski
mesh_terms: D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000494:pharmacology*; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D002762:Cholecalciferol
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