Plant flavonoid apigenin inactivates Akt to trigger apoptosis in human prostate cancer: an in vitro and in vivo study.
Plant flavonoid apigenin inactivates Akt to trigger apoptosis in human prostate cancer: an in vitro and in vivo study.
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DOI：
10.1093/carcin/bgn201
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发表时间：
2008-11
期刊：
影响因子：
4.7
通讯作者：
Gupta S
中科院分区：
文献类型：
--
作者：
Kaur P;Shukla S;Gupta S
PI3K/Akt 信号传导的不当激活会导致多种人类恶性肿瘤的发生。调节 Akt 活性是一种在化学预防和化疗方案中可能有价值的策略。我们之前已经证明芹菜素（一种植物黄酮）会导致人类前列腺癌细胞的存活率降低。然而，这一观察结果背后的分子机制仍然难以捉摸。在本研究中，我们研究了芹菜素对具有组成型活性 Akt 的人前列腺癌 PC-3 细胞的作用机制。用芹菜素 (5–40μM) 处理 PC-3 细胞会导致 Akt 丝氨酸 473 磷酸化显着降低，呈剂量和时间依赖性。芹菜素介导的 Akt 去磷酸化导致其激酶活性受到抑制，这一点通过促凋亡蛋白 BAD 和糖原合酶激酶 3（Akt 的重要下游靶标）的磷酸化减少得到证实。将 20μM 芹菜素暴露于 PC-3 细胞 24 小时后，BAD 的低磷酸化导致与 14-3-3β 蛋白的相互作用减少。 Akt 失活似乎与芹菜素治疗后胰岛素样生长因子受体 1 蛋白水平的下调及其自身磷酸化的抑制有关。暴露于芹菜素可显着诱导 caspase-9 活性，并以剂量依赖性方式降低 PC-3 细胞的存活率。此外，DU145 细胞中异位表达的 Akt 的 Serine473 磷酸化在 20μM 芹菜素处理后显着降低。在体内，通过灌胃摄入芹菜素会导致 Akt 失活并诱导 PC-3 肿瘤细胞凋亡。这些结果表明，Akt 失活和 BAD 去磷酸化是芹菜素诱导的细胞存活率下降和细胞凋亡的关键事件（至少部分如此）。
Inappropriate activation of PI3K/Akt signaling contributes to the development of several human malignancies. Modulation of Akt activity is a strategy that may be valuable in chemopreventive and chemotherapeutic regimens. We have previously demonstrated that apigenin, a plant flavone, causes decreased survival in human prostate cancer cells. However, the molecular mechanism underlying this observation remains elusive. In the present study, we investigated the mechanism(s) of apigenin action on human prostate cancer PC-3 cells, which possess constitutively active Akt. Treatment of PC-3 cells with apigenin (5–40µM) resulted in significant dose- and time- dependent decrease in Akt phosphorylation at Serine473. Apigenin-mediated dephosphorylation of Akt resulted in inhibition of its kinase activity, which was confirmed by reduced phosphorylation of pro-apoptotic proteins BAD and glycogen synthase kinase-3, essential downstream targets of Akt. Hypophosphorylation of BAD resulted in reduced interaction with 14-3-3β protein after 20µM apigenin exposure to PC-3 cells for 24 h. Inactivation of Akt seems to be associated with downregulation of insulin-like growth factor receptor 1 protein level and inhibition of its autophosphorylation upon apigenin treatment. Exposure to apigenin significantly induced caspase-9 activity and decreased the survival of PC-3 cells in a dose-dependent manner. Furthermore, Serine473 phosphorylation of ectopically expressed Akt in DU145 cells was significantly reduced upon 20µM apigenin treatment. In vivo, apigenin intake through gavage resulted in inactivation of Akt and induction of apoptosis in PC-3 tumors. These results suggest that Akt inactivation and dephosphorylation of BAD is a critical event, at least in part, in apigenin-induced decreased cell survival and apoptosis.
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影响因子：
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