Rapamycin Regulates Akt and ERK Phosphorylation Through mTORC1 and mTORC2 Signaling Pathways
Rapamycin Regulates Akt and ERK Phosphorylation Through mTORC1 and mTORC2 Signaling Pathways
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DOI：
10.1002/mc.20628
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发表时间：
2010-06-01
影响因子：
4.6
通讯作者：
Zhuang, Qian-Yuan
中科院分区：
文献类型：
--
作者：
Chen, Xian-Guo;Liu, Fei;Zhuang, Qian-Yuan
大量研究表明，哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂通过负反馈环激活Akt信号通路，同时抑制mTORC 1信号通路。在这篇报告中，我们重点研究了mTORC 1和mTORC 2在雷帕霉素介导的Akt和ERK磷酸化中的作用，以及雷帕霉素与Akt和ERK抑制剂联合应用对癌细胞的抗肿瘤作用。此外，我们还分析了mTORC 1和mTORC 2在调节细胞周期进程中的作用。我们发现，低浓度的雷帕霉素通过mTORC 1依赖的机制增加Akt和ERK的磷酸化，因为敲低的raptor诱导Akt和ERK的激活，但较高剂量的雷帕霉素主要通过mTORC 2信号通路抑制Akt和ERK的磷酸化，因为rictor的沉默导致Akt和ERK磷酸化的抑制。我们进一步表明mTORC 2通过Akt依赖性机制与细胞周期的发展密切相关。因此，我们将PI 3 K和ERK抑制剂组合防止雷帕霉素诱导的Akt活化并增强雷帕霉素的抗肿瘤作用。总的来说，我们得出结论，mTORC 2发挥了更重要的作用比mTORC 1在雷帕霉素介导的Akt和ERK的磷酸化，和cotargeting AKT和ERK信号转导可能是一个新的策略，提高雷帕霉素为基础的治疗方法在癌细胞中的疗效。(C)2010 Wiley-Liss，Inc.
Numerous studies have shown that mammalian target of rapamycin (mTOR) inhibitor activates Akt signaling pathway via a negative feedback loop while inhibiting mTORC1 signaling. In this report, we focused on studying the role of mTORC1 and mTORC2 in rapamycin-mediated Akt and ERK phosphorylation, and the antitumor effect of rapamycin in cancer cells in combination with Akt and ERK inhibitors. Moreover, we analyzed the effect of mTORC1 and mTORC2 on regulating cell cycle progression. We found that low concentrations rapamycin increased Akt and ERK phosphorylation through a mTORC1-dependent mechanism because knockdowned raptor induced the activation of Akt and ERK, but higher doses of rapamycin inhibited Akt and ERK phosphorylation mainly via the mTORC2 signaling pathway because that the silencing of rictor led to the inhibition of Akt and ERK phosphorylation. We further showed that mTORC2 was tightly associated with the development of cell cycle through an Akt-dependent mechanism. Therefore, we combined PI3K and ERK inhibitors prevent rapamycin-induced Akt activation and enhanced antitumor effects of rapamycin. Collectively, we conclude that mTORC2 plays a much more important role than mTORC1 in rapamycin-mediated phosphorylation of Akt and ERK, and cotargeting AKT and ERK signaling may be a new strategy for enhancing the efficacy of rapamycin-based therapeutic approaches in cancer cells. (C) 2010 Wiley-Liss, Inc.