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雄激素受体(androgenreceptor,AR)作为核转录因子,其高表达、基因突变以及AR辅激活因子的过表达等造成AR的异常激活与前列腺癌细胞的增殖、恶化转移、多药耐药等密切相关.天然黄酮槲皮素(quercetin),是一很有潜力的预防和治疗前列腺肿瘤的化合物.槲皮素不仅抑制前列腺癌细胞LNCaP的增殖,并呈剂量依赖性,而且下调前列腺癌中AR的表达、抑制AR的转录激活功能.GCbox是AR核心启动子的主要正调控元件,是转录因子Sp1的结合位点.细胞转染结果表明,槲皮素能抑制Sp1蛋白对AR启动子的激活作用,可能是槲皮素下调AR表达的机理之一.进一步研究显示,槲皮素还能明显抑制Sp1蛋白对AR转录激活功能的增强作用.Western印迹结果显示,槲皮素对Sp1蛋白表达无明显影响,但能够诱导c-Jun的高表达,而高表达的c-Jun蛋白能逆转Sp1蛋白对AR的转录激活作用,由此推测,槲皮素可能通过介导c-Jun与Sp1的蛋白质相互作用,抑制Sp1的功能,进而起到抑制AR表达和功能的作用.免疫沉淀结果又进一步证实了Sp1与c-Jun二者的相互作用.因此,槲皮素可能通过抑制前列腺癌细胞中AR的表达和功能抑制了细胞的增殖,其分子机理可能与槲皮素诱导的c-Jun与Sp1蛋白相互作用、降低Sp1对AR的转录激活作用有关.
The abnormal activation of AR caused by androgen receptor (AR) as a nuclear transcription factor, its high expression, gene mutation and AR coactivator overexpression is associated with the proliferation, metastasis and multidrug resistance of prostate cancer cells Quercetin, a promising compound for the prevention and treatment of prostate tumors.Quercetin not only inhibits the proliferation of prostate cancer cell line LNCaP in a dose-dependent manner, but also down-regulates the expression of AR in prostate cancer Expression and inhibit the transcriptional activation of AR.GCbox is the main positive regulatory element of AR core promoter and the binding site of transcription factor Sp1.Transfection results showed that quercetin can inhibit the activation of Sp1 protein on AR promoter , May be quercetin one of the mechanisms of down-regulation of AR expression.Further study showed that quercetin also significantly inhibited the Sp1 protein AR enhanced transcriptional activation.Western blot results showed that quercetin had no significant effect on Sp1 protein expression But could induce the high expression of c-Jun, while high expression of c-Jun protein can reverse the transcriptional activation of Sp1 protein on AR, suggesting that quercetin may mediate c-Jun and Sp 1 protein interaction, inhibit the function of Sp1, and thus play a role in the inhibition of AR expression and function.Immunoprecipitation results further confirmed the interaction between Sp1 and c-Jun.Therefore, quercetin may inhibit prostate cancer AR expression and function in cells inhibited the proliferation of cells, the molecular mechanism may be quercetin-induced interaction of c-Jun and Sp1 protein, reducing Sp1 AR transcriptional activation.