Perifosine enhances mTORC1-targeted cancer therapy by activation of GSK3β in NSCLC cells
Perifosine enhances mTORC1-targeted cancer therapy by activation of GSK3β in NSCLC cells
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DOI：
10.4161/cbt.20989
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发表时间：
2012-09-01
影响因子：
3.6
通讯作者：
Wang, Xuerong
中科院分区：
文献类型：
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作者：
Ma, Zhuo;Zhu, Lingjun;Wang, Xuerong
mTORC 1抑制剂，包括雷帕霉素及其类似物，已经在临床前和临床上进行了积极的研究。然而，mTORC 1抑制剂的单一治疗在大多数癌症类型中是适度的。我们之前已经证明了PI 3 K/Akt和MEK/ERK信号通路的激活减弱了mTORC 1抑制剂的抗癌功效。在这项研究中，我们报告mTORC 1抑制也磷酸化和失活GSK 3 β，这是肺癌的肿瘤抑制因子。此外，我们发现哌立福辛作为Akt抑制剂，降低雷帕霉素诱导的GSK 3 β磷酸化和雷帕霉素抗性细胞系中p-GSK 3 β水平升高。哌立福辛与mTORC 1抑制剂的组合在细胞培养物和异种移植小鼠模型中均显示出增强的抗癌功效。此外，哌立福新抑制雷帕霉素敏感性和抗性A549细胞的生长。然而，通过选择性阻断剂-LiCl抑制GSK 3 β或通过siRNA下调GSK 3 β表达，逆转了哌立福新对雷帕霉素抗性细胞的生长抑制作用，表明GSK 3 β活化在哌立福新增强mTORC 1抑制剂功效中的重要作用。因此，我们的研究结果提供了一种潜在的治疗策略，通过使用哌立福新或靶向GSK 3 β来增强mTORC 1靶向癌症治疗。
mTORC1 inhibitors, including rapamycin and its analogs, have been actively studied both pre-clinically and clinically. However, the single treatment of mTORC1 inhibitors has been modest in most cancer types. We have previously demonstrated that the activation of PI3K/Akt and MEK/ERK signaling pathways attenuates the anticancer efficacy of mTORC1 inhibitors. In this study, we report that mTORC1 inhibition also phosphorylates and inactivates GSK3 beta, which is a tumor suppressor in lung cancer. Moreover, we show that perifosine, as an Akt inhibitor, decreases rapamycin-induced phosphorylation of GSK3 beta and elevated p-GSK3 beta levels in rapamycin-resistant cell lines. Combination of perifosine with mTORC1 inhibitors showed enhanced anticancer efficacy both in cell cultures and in a xenograft mouse model. In addition, perifosine inhibits the growth of both rapamycin sensitive and resistant A549 cells. However, inhibition of GSK3 beta by a selective inhibitor-LiCl, or downregulation of GSK3 beta expression by siRNA, reverses the growth inhibitory effects of perifosine on rapamycin resistant cells, suggesting the important role of GSK3 beta activation in enhancing mTORC1 inhibitors efficacy by perifosine. Thus, our results provide a potential therapeutic strategy to enhance mTORC1-targeted cancer therapy by using perifosine or targeting GSK3 beta.