Marine Science Institute, University of Texas at Austin, 750 Channel View Drive, Port Aransas, TX, 78373, United States.
Marine Science Institute, University of Texas at Austin, 750 Channel View Drive, Port Aransas, TX, 78373, United States.
J Steroid Biochem Mol Biol. 2021 Jul;211:105906. doi: 10.1016/j.jsbmb.2021.105906. Epub 2021 May 11.
(-)-Epicatechin, a flavonoid present in high concentrations in foods such as green tea and cocoa, exerts beneficial and protective effects in numerous disease models, including anti-tumorigenesis and apoptosis in human breast and prostate cancer cells. Potential interactions of (-)-epicatechin and (+)-catechin with the membrane androgen receptor, ZIP9 (SLC39A9), which mediates androgen induction of apoptosis in these cancer cells, were investigated. Both (-)-epicatechin and (+)-catechin were effective competitors of [H]-testosterone binding to PC-3 prostate cancer cells (nuclear androgen receptor-negative, nAR-null) overexpressing ZIP9 (PC3-ZIP9), with relative binding affinities of 75 % and 28 % that of testosterone, respectively. (-)-Epicatechin (200 nM) mimicked the effects of 100 nM testosterone in inducing apoptosis of PC3-ZIP9 cells, whereas (+)-catechin (concentration range 200 nM-1000 nM) did not significantly increase apoptosis and instead blocked the apoptotic response to testosterone. (-)-Epicatechin also activated androgen-dependent ZIP9 signaling pathways, inducing decreases in cAMP production and elevating intracellular free zinc levels, while (+)-catechin typically lacked these actions. Both (-)-epicatechin and (+)-catechin also bound to cell membranes of MDA-MB-468 breast cancer cells (nAR-null, high ZIP9 expression). MDA-MB-468 cells showed similar apoptotic, cAMP, and free zinc signaling responses to (-)-epicatechin to those observed in PC3-ZIP9 cells, as well as antagonism by (+)-catechin of testosterone-induced apoptosis and modulation of cAMP and caspase-3 levels. Moreover, knockdown of ZIP9 expression in MDA-MB-468 cells with siRNA decreased specific [H]-testosterone binding of both catechins and blocked the apoptotic and free zinc responses to testosterone and (-)-epicatechin. The results indicate (-)-epicatechin is a potent ZIP9 agonist in breast and prostate cancer cells.
（-）-表儿茶素是一种在绿茶和可可等食物中含量很高的类黄酮，它对多种疾病模型具有有益和保护作用，包括抑制人类乳腺癌和前列腺癌细胞的肿瘤发生和凋亡。研究了（-）-表儿茶素和（+）-儿茶素与介导这些癌细胞中雄激素诱导凋亡的膜雄激素受体 ZIP9（SLC39A9）的潜在相互作用。（-）-表儿茶素和（+）-儿茶素均能有效竞争[H]-睾酮与过表达 ZIP9（PC3-ZIP9）的 PC-3 前列腺癌细胞（核雄激素受体阴性，nAR-缺失）的结合，其相对结合亲和力分别为睾酮的 75%和 28%。（-）-表儿茶素（200 nM）模拟了 100 nM 睾酮诱导 PC3-ZIP9 细胞凋亡的作用，而（+）-儿茶素（浓度范围 200 nM-1000 nM）则不能显著增加细胞凋亡，反而阻断了对睾酮的凋亡反应。（-）-表儿茶素还激活了雄激素依赖性的 ZIP9 信号通路，诱导 cAMP 产生减少和细胞内游离锌水平升高，而（+）-儿茶素通常缺乏这些作用。（-）-表儿茶素和（+）-儿茶素也与 MDA-MB-468 乳腺癌细胞（nAR-缺失，ZIP9 高表达）的细胞膜结合。MDA-MB-468 细胞对（-）-表儿茶素的凋亡、cAMP 和游离锌信号反应与在 PC3-ZIP9 细胞中观察到的反应相似，（+）-儿茶素也拮抗了睾酮诱导的凋亡并调节了 cAMP 和 caspase-3 水平。此外，用 siRNA 敲低 MDA-MB-468 细胞中的 ZIP9 表达，减少了两种儿茶素的特异性[H]-睾酮结合，并阻断了对睾酮和（-）-表儿茶素的凋亡和游离锌反应。结果表明，（-）-表儿茶素是乳腺癌和前列腺癌细胞中一种有效的 ZIP9 激动剂。
