Formononetin Promotes Cell Cycle Arrest via Downregulation of Akt/Cyclin D1/CDK4 in Human Prostate Cancer Cells
Formononetin Promotes Cell Cycle Arrest via Downregulation of Akt/Cyclin D1/CDK4 in Human Prostate Cancer Cells
复制标题
芒柄花素通过下调人前列腺癌细胞中的 Akt/Cyclin D1/CDK4 促进细胞周期停滞
DOI：
10.1159/000366342
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发表时间：
2014-01-01
影响因子：
--
通讯作者：
Ye, Yu
中科院分区：
文献类型：
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作者：
Li, Tianyu;Zhao, Xinge;Ye, Yu
背景：芒柄花素是从黄芪根部分离得到的一种O-甲基化异黄酮类化合物。已有研究报道芒柄花素可抑制细胞增殖，诱导包括前列腺癌在内的多种癌症的细胞凋亡。本研究旨在进一步探讨芒柄花素对人前列腺癌细胞的抗肿瘤作用是否与细胞周期停滞有关，并探讨其分子机制。方法：将不同浓度芒柄花素分别作用于人前列腺癌PC-3和DU145细胞。采用四甲基偶氮唑盐比色法和流式细胞仪检测芒柄花素对前列腺癌细胞增殖的抑制作用。采用实时定量聚合酶链式反应和免疫印迹法检测芒柄花素对PC-3细胞周期蛋白D1、CDK4和Akt表达的影响。结果：在体外，芒柄花素通过诱导细胞周期停滞于G0/G1期而抑制前列腺癌细胞的增殖，这种抑制作用在PC-3细胞中更为明显。同时，伴随着PC-3细胞Akt磷酸化水平的降低，芒柄花素显著下调Cyclin D1和CDK4的表达水平，并呈剂量依赖关系。更有趣的是，在体内研究中，芒柄花素对受体小鼠的肿瘤生长有明显的抑制作用。结论：芒柄花素在体内外对人前列腺癌细胞具有抑制作用，其机制可能与Akt/Cyclin D1/CDK4失活使细胞周期停滞于G1期有关。因此，芒柄花素有可能作为前列腺癌临床治疗的候选药物。
Background: Formononetin is an O-methylated isoflavone isolated from the root of Astragalus membranaceus. It has already been reported that formononetin could inhibit cell proliferation and induce cell apoptosis in several cancers, including prostate cancer. This study aimed to further investigate whether cell cycle arrest is involved in formononetin-mediated antitumor effect in human prostate cancer cells, along with the underlying molecular mechanism. Methods: Human prostate cancer cells PC-3 and DU145 were respectively treated with various concentrations of formononetin. The inhibitory effect of formononetin on proliferation of prostate cancer cells was determined using MTT assays and flow cytometry. Next, formononetin-induced alterations in cyclin D1, CDK4 and Akt expression in PC-3 cells were detected by real-time PCR and western blot. Results: Formononetin dose-dependently inhibited prostate cancer cell proliferation via the induction of cell cycle arrest at G0/G1 phase in vitro, which was more evident in PC-3 cells. Meanwhile, concomitant with reduced phosphorylation of Akt in PC-3 cells, formononetin remarkably downregulated expression levels of cyclin D1 and CDK4 in a dose-dependent manner. More interestingly, in the in vivo studies, formononetin showed a noticeable inhibition of tumor growth in recipient mice. Conclusion: Formononetin could exhibit inhibitory activity against human prostate cancer cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of Akt/cyclin D1/CDK4. Therefore, formononetin may be used as a candidate agent for clinical treatment of prostate cancer in the future.