Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism
Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism
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DOI：
10.1038/sj.onc.1209990
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发表时间：
2007-03-22
期刊：
影响因子：
8
通讯作者：
Helman, L. J.
中科院分区：
文献类型：
--
作者：
Wan, X.;Harkavy, B.;Helman, L. J.
雷帕霉素和几种类似物，如CCI-779和RAD 001，目前正在进行临床评价作为抗癌剂。在这项研究中，我们发现，雷帕霉素抑制哺乳动物雷帕霉素靶蛋白（mTOR）信号转导导致Akt磷酸化增加Rh 30和RD人横纹肌肉瘤细胞系和异种移植物，胰岛素样生长因子（IGF）-II处理的C2 C12小鼠成肌细胞和IGF-II过表达的中国仓鼠卵巢细胞。RNA干扰介导的S6 K1敲低也导致Akt磷酸化的增加。这些数据表明，通过雷帕霉素或小干扰RNA（siRNA）抑制mTOR/S6 K1触发负反馈回路，导致Akt信号传导的激活。接下来，我们试图研究从mTOR到Akt的这种负反馈调节的机制。抑制胰岛素受体底物（IRS）-1和结节性硬化症复合物-1的siRNA未能废除雷帕霉素诱导的Akt磷酸化的上调在Rh 30和RD细胞。然而，用针对胰岛素样生长因子-1受体（IGF-1 R）的h7 C10抗体预处理导致雷帕霉素诱导的Akt活化的阻断。分别用雷帕霉素和h7 C10抗体组合mTOR和IGF-1 R抑制，导致细胞生长和存活的叠加抑制。这些数据表明，雷帕霉素介导的Akt激活通过IGF-1 R依赖性机制。因此，组合mTOR抑制剂和IGF-1 R抗体/抑制剂可能是增强mTOR靶向抗癌疗法的适当策略。
Rapamycin and several analogs, such as CCI-779 and RAD001, are currently undergoing clinical evaluation as anticancer agents. In this study, we show that inhibition of mammalian target of rapamycin ( mTOR) signaling by rapamycin leads to an increase of Akt phosphorylation in Rh30 and RD human rhabdomyosarcoma cell lines and xenografts, and insulin-like growth factor (IGF)-II-treated C2C12 mouse myoblasts and IGF-II-overexpressing Chinese hamster ovary cells. RNA interference-mediated knockdown of S6K1 also results in an increase of Akt phosphorylation. These data suggest that mTOR/S6K1 inhibition either by rapamycin or small interfering RNA ( siRNA) triggers a negative feedback loop, resulting in the activation of Akt signaling. We next sought to investigate the mechanism of this negative feedback regulation from mTOR to Akt. Suppression of insulin receptor substrate (IRS)-1 and tuberous sclerosis complex-1 by siRNAs failed to abrogate rapamycin-induced upregulation of Akt phosphorylation in both Rh30 and RD cells. However, pretreatment with h7C10 antibody directed against insulin-like growth factor-1 receptor (IGF-1R) led to a blockade of rapamycin-induced Akt activation. Combined mTOR and IGF-1R inhibition with rapamycin and h7C10 antibody, respectively, resulted in additive inhibition of cell growth and survival. These data suggest that rapamycin mediates Akt activation through an IGF-1R-dependent mechanism. Thus, combining an mTOR inhibitor and an IGF-1R antibody/inhibitor may be an appropriate strategy to enhance mTOR-targeted anticancer therapy.