Akt-GSK-3 pathway as a target in genistein-induced inhibition of TRAMP prostate cancer progression toward a poorly differentiated phenotype
Akt-GSK-3 pathway as a target in genistein-induced inhibition of TRAMP prostate cancer progression toward a poorly differentiated phenotype
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DOI：
10.1093/carcin/bgm103
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发表时间：
2007-08-01
期刊：
影响因子：
4.7
通讯作者：
Banerjee, Partha P.
中科院分区：
文献类型：
--
作者：
El Touny, Lara. H.;Banerjee, Partha P.
染料木黄酮在前列腺和其他癌症中的抗增殖特性已被广泛研究。然而，染料木黄酮的目标，可能介导其在体内的化学预防作用的鉴定需要进一步阐明。在这项研究中，我们已经证明，染料木黄酮在转基因腺癌小鼠前列腺模型（TRAMP/FVB）小鼠的饮食中的掺入导致前列腺大小的减少和低分化（PD）癌的发生率，随后在前列腺上皮内瘤（PIN）阶段前列腺的积累。TRAMP/ FVB前列腺癌进展和PD癌症发作的特征在于啮齿动物T细胞淋巴瘤（Akt）中急性转化逆转录病毒AKT 8的激活、糖原合成酶激酶3-β（GSK-3 β）的磷酸化、细胞周期蛋白D1的转录后上调以及通过snail-1上调抑制钙粘蛋白-1。在饮食中掺入染料木黄酮显著抑制Akt的活化，恢复GSK-3 β的活化，降低细胞周期蛋白D1的转录后水平，并通过下调snail-1维持钙粘蛋白-I复合物的表达。通过鉴定Akt-GSK-3通路及其下游效应物作为染料木黄酮化学预防作用的靶点，我们阐明了染料木黄酮降低增殖潜力、延缓癌症进展并维持体内前列腺上皮细胞完整性的一种可能机制。
Anti-proliferative properties of genistein in prostate and other cancers have been studied extensively. However, the identification of genistein targets that may mediate its chemopreventive effects in vivo requires further elucidation. In this study, we have demonstrated that the incorporation of genistein in the diet of transgenic adenocarcinoma mouse prostate model (TRAMP/FVB) mice resulted in a reduction in prostate size and the incidence of poorly differentiated (PD) cancer ensuing in an accumulation of prostates at the prostatic intra-epithelial neoplasia (PIN) stage. TRAMP/ FVB prostate cancer progression and the onset of PD cancer were characterized by the activation of acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt), phosphorylation of glycogen synthase kinase 3-beta (GSK-3 beta), post-transcriptional up-regulation of cyclin D1 and repression of cadherin-1 via snail-1 up-regulation. Incorporation of genistein in the diet significantly inhibited the activation of Akt, restored the activation of GSK-3 beta, reduced cyclin D1 levels post-transcriptionally and maintained the expression of the cadherin-I complex via down-regulation of snail-1. By identifying the Akt-GSK-3 pathway and subsequently its downstream effectors, as targets for genistein chemopreventive action, we have elucidated one possible mechanism by which genistein decreases the proliferative potential, retards cancer progression and maintains the integrity of the prostatic epithelial cells in vivo.