High basal NF-κB activity in nonpigmented melanoma cells is associated with an enhanced sensitivity to vitamin D3 derivatives
High basal NF-κB activity in nonpigmented melanoma cells is associated with an enhanced sensitivity to vitamin D3 derivatives
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DOI：
10.1038/bjc.2011.458
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发表时间：
2011-12-06
影响因子：
8.8
通讯作者：
Slominski, A. T.
中科院分区：
文献类型：
--
作者：
Janjetovic, Z.;Brozyna, A. A.;Slominski, A. T.
背景技术背景：黑色素瘤对目前的治疗方式具有高度抗性，色素沉着的程度在治疗抗性中起重要作用。核因子-κ B（NF-κ B）是组成性激活的黑色素瘤，可以作为一个分子靶点的癌症治疗和类固醇/开环类固醇action.METHODS：培养的黑色素瘤细胞用于NF-κ B活性的机制研究，利用免疫荧光，蛋白质印迹，EMSA，ELISA，基因报告，估计DNA合成分析。结果：新型20-羟基维生素（20（OH）D（3））和经典的1 α，25-二羟基维生素D（3）（1，25（OH）（2）D（3））开环甾体类化合物抑制黑素瘤细胞增殖。发现活性形式的维生素D抑制非色素细胞中的NF-κ B活性，而对色素细胞没有影响。用维生素D3衍生物处理非色素细胞抑制NF-κ B B DNA结合和NF-κ B依赖性报告基因测定，以及抑制p65 NF-κ B亚基的核转位及其在细胞质中的积累。此外，黑色素瘤患者的活检分析表明，nonpigmented和轻度色素性黑色素瘤显示较高的核NF-κ B p65的表达比高度色素性melanoma.CONCLUSION：经典的1，25（OH）（2）D（3）和新的20（OH）D（3）维生素D3的羟基衍生物可以靶向NF-κ B和调节黑色素瘤的进展在nonpigmented黑色素瘤细胞。黑色素沉着与黑色素瘤对20（OH）D（3）和1，25（OH）（2）D（3）治疗的抗性有关。英国癌症杂志（2011）105，1874-1884。doi：10.1038/bjc.2011.458 www.bjcancer.com在线发布2011年11月17日（C）2011英国癌症研究
BACKGROUND: Melanoma is highly resistant to current modalities of therapy, with the extent of pigmentation playing an important role in therapeutic resistance. Nuclear factor-kappa B (NF-kappa B) 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-kappa 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-kappa B activity in situ.RESULTS: Novel 20-hydroxyvitamin (20(OH)D(3)) and classical 1 alpha,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-kappa B activity in nonpigmented cells, while having no effect on pigmented cells. Treatment of nonpigmented cells with vitamin D3 derivatives inhibited NF-kappa B DNA binding and NF-kappa B-dependent reporter assays, as well as inhibited the nuclear translocation of the p65 NF-kappa 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-kappa B 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-kappa 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)(2)D(3) treatment. British Journal of Cancer (2011) 105, 1874-1884. doi: 10.1038/bjc.2011.458 www.bjcancer.com Published online 17 November 2011 (C) 2011 Cancer Research UK