Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin.
Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin.
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DOI：
10.1002/ijc.26178
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发表时间：
2012-04-01
影响因子：
6.4
通讯作者：
Mukhtar, Hasan
中科院分区：
文献类型：
--
作者：
Khan, Naghma;Afaq, Farrukh;Khusro, Fatima H.;Adhami, Vaqar Mustafa;Suh, Yewseok;Mukhtar, Hasan
肺癌是最常见的恶性肿瘤之一。据报道，mTOR 在肺癌中被磷酸化，并且在 PI3K/Akt 过度表达的肿瘤中其激活更为频繁。因此，PI3K/Akt 和 mTOR 信号传导的双重抑制剂可能是治疗肺癌的有价值的药物。在本研究中，我们发现非瑟酮（一种膳食四羟基黄酮）可抑制人类非小细胞肺癌 (NSCLC) 细胞的细胞生长，同时抑制 PI3K/Akt 和 mTOR 信号传导。使用 autodock 4，我们发现非瑟酮与 mTOR 复合物在两个位点发生物理相互作用。还发现非瑟酮治疗可以剂量依赖性方式减少 A549 细胞集落的形成。用非瑟酮处理细胞会导致 PI3K（p85 和 p110）蛋白表达降低，Akt、mTOR、p70S6K1、eIF-4E 和 4E-BP1 磷酸化受到抑制。非瑟酮处理的细胞还表现出对 mTOR 信号复合物（如 Rictor、Raptor、GβL 和 PRAS40）成分的剂量依赖性抑制。用非瑟酮处理细胞后，AMPKα 磷酸化增加，TSC2 磷酸化减少。我们还发现，用 mTOR 抑制剂雷帕霉素和 mTOR-siRNA 处理细胞会导致 mTOR 及其靶蛋白的磷酸化降低，而用非瑟酮处理后，mTOR 及其靶蛋白的磷酸化会进一步下调，表明这些作用部分是通过 mTOR 信号传导介导的。我们的结果表明，非瑟酮抑制 NSCLC 细胞中的 PI3K/Akt 和 mTOR 信号传导，因此可以开发为针对人类肺癌的化疗剂。
Lung cancer is one of the most commonly occurring malignancies. It has been reported that mTOR is phosphorylated in lung cancer and its activation was more frequent in tumors with over-expression of PI3K/Akt. Therefore, dual inhibitors of PI3K/Akt and mTOR signaling could be valuable agents for treating lung cancer. In the present study, we show that fisetin, a dietary tetrahydroxyflavone inhibits cell-growth with the concomitant suppression of PI3K/Akt and mTOR signaling in human non-small cell lung cancer (NSCLC) cells. Using autodock 4, we found that fisetin physically interacts with the mTOR complex at two sites. Fisetin treatment was also found to reduce the formation of A549 cell colonies in a dose-dependent manner. Treatment of cells with fisetin caused decrease in the protein expression of PI3K (p85 and p110), inhibition of phosphorylation of Akt, mTOR, p70S6K1, eIF-4E and 4E-BP1. Fisetin-treated cells also exhibited dose-dependent inhibition of the constituents of mTOR signaling complex like Rictor, Raptor, GβL and PRAS40. There was increase in the phosphorylation of AMPKα and decrease in the phosphorylation of TSC2 on treatment of cells with fisetin. We also found that treatment of cells with mTOR inhibitor rapamycin and mTOR-siRNA caused decrease in phosphorylation of mTOR and its target proteins which were further downregulated on treatment with fisetin, suggesting that these effects are mediated in part, through mTOR signaling. Our results show that fisetin suppressed PI3K/Akt and mTOR signaling in NSCLC cells and thus, could be developed as a chemotherapeutic agent against human lung cancer.
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DOI：
10.1083/jcb.200403069
发表时间：
2004-07-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrington LS;Findlay GM;Gray A;Tolkacheva T;Wigfield S;Rebholz H;Barnett J;Leslie NR;Cheng S;Shepherd PR;Gout I;Downes CP;Lamb RF
通讯作者：
Lamb RF
影响因子：
82.9
作者：
Ruggero, D;Montanaro, L;Pandolfi, PP
通讯作者：
Pandolfi, PP
影响因子：
6.4
作者：
Murtaza, Imtiyaz;Adhami, Vaqar Mustafa;Bin Hafeez, Bilal;Saleem, Mohammad;Mukhtar, Hasan
通讯作者：
Mukhtar, Hasan
影响因子：
6.1
作者：
Chen, YC;Shen, SC;Yang, LL
通讯作者：
Yang, LL
DOI：
10.1073/pnas.0607822103
发表时间：
2006-10-31
影响因子：
11.1
作者：
Maher, Pamela;Akaishi, Tatsuhiro;Abe, Kazuho
通讯作者：
Abe, Kazuho