Blockade of β-catenin signaling by plant flavonoid apigenin suppresses prostate carcinogenesis in TRAMP mice
Blockade of β-catenin signaling by plant flavonoid apigenin suppresses prostate carcinogenesis in TRAMP mice
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DOI：
10.1158/0008-5472.can-07-0717
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发表时间：
2007-07-15
期刊：
影响因子：
11.2
通讯作者：
Gupta, Sanjay
中科院分区：
文献类型：
--
作者：
Shukla, Sanjeev;MacLennan, Gregory T.;Gupta, Sanjay
β-连环蛋白信号的去调控在包括前列腺癌在内的几种人类恶性肿瘤的发生中是一个重要事件。我们研究了芹菜素，一种天然存在的植物黄酮素，对流浪鼠前列腺癌发生的影响，并进一步阐明了其作用机制。口服芹菜素20和50微克/鼠/天，每周6天，连续20周，可显著减少前列腺肿瘤体积，并完全消除小鼠淋巴结、肺和肝脏的远处转移。与对照组相比，芹菜素处理组小鼠的泌尿生殖器官以及背外侧和腹侧前列腺叶的重量显著减轻，前列腺背外侧的增殖减少和细胞凋亡增加，这与血浆芹菜素水平的升高有关。流浪鼠持续摄入芹菜素长达50周，显著提高了它们的总体存活率。邮政总局给药后，TraMP小鼠前列腺背外侧区E-钙粘附素水平升高，核β-连环素、c-Myc和细胞周期蛋白D1水平降低。在已有肿瘤的流浪鼠身上也观察到了类似的效果。用10和20mU·mol/L芹菜素处理人前列腺癌DU145细胞后，E-钙粘附素的蛋白水平升高27%~74%，抑制β-连环素的核转位和胞质内滞留，降低c-Myc和细胞周期蛋白D1的水平，其作用类似于细胞暴露于β-连环素小干扰RNA。我们的结果表明，芹菜素有效地抑制了流浪鼠前列腺癌的发生，至少部分是通过阻断β-连环蛋白信号。
Deregulation of beta-catenin signaling is an important event in the genesis of several human malignancies including prostate cancer. We investigated the effects of apigenin, a naturally occurring plant flavone, on prostate carcinogenesis in TRAMP mice and further elucidated its mechanism of action. Oral intake of apigenin by gavage at doses of 20 and 50 mu g/mouse/d, 6 days per week for 20 weeks, significantly decreased tumor volumes of the prostate as well as completely abolished distant-site metastases to lymph nodes, lungs, and liver in TRAMP mice. Apigenin-treated mice had significantly diminished weights of their genitourinary apparatuses and dorsolateral and ventral prostate lobes, compared with the control group, and showed reduced proliferation and increased apoptosis in the dorsolateral prostates, which correlated with elevated plasma apigenin levels. Continuous intake of apigenin up to 50 weeks by TRAMP mice significantly improved their overall survival. P.o. administration of apigenin further resulted in increased levels of E-cadherin and decreased levels of nuclear beta-catenin, c-Myc, and cyclin D1 in the dorsolateral prostates of TRAMP mice. Similar effects were noted in TRAMP mice with established tumors. Treatment of DU145 human prostate cancer cells with 10 and 20 mu mol/L apigenin also increased protein levels of E-cadherin by 27% to 74%, inhibited nuclear translocation of beta-catenin and its retention in the cytoplasm, and decreased c-Myc and cyclin D1 levels, an effect similar to the exposure of cells to beta-catenin small interfering RNA. Our results indicate that apigenin effectively suppressed prostate carcinogenesis in TRAMP mice, at least in part, by blocking beta-catenin signaling.