Inhibition of mTORC2 Induces Cell-Cycle Arrest and Enhances the Cytotoxicity of Doxorubicin by Suppressing MDR1 Expression in HCC Cells.
Inhibition of mTORC2 Induces Cell-Cycle Arrest and Enhances the Cytotoxicity of Doxorubicin by Suppressing MDR1 Expression in HCC Cells.
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抑制 mTORC2 可诱导细胞周期停滞，并通过抑制 HCC 细胞中 MDR1 的表达来增强阿霉素的细胞毒性
DOI：
10.1158/1535-7163.mct-15-0029
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发表时间：
2015-08
影响因子：
5.7
通讯作者：
Liang TB
中科院分区：
文献类型：
--
作者：
Chen BW;Chen W;Liang H;Liu H;Liang C;Zhi X;Hu LQ;Yu XZ;Wei T;Ma T;Xue F;Zheng L;Zhao B;Feng XH;Bai XL;Liang TB
mTOR在肝细胞癌（HCC）中异常激活，并在肿瘤发生和化疗耐药性中起关键作用。据报道，雷帕霉素在HCC中发挥抗肿瘤活性，并使HCC细胞对细胞毒性剂敏感。然而，由于mTOR复合物1（mTORC 1）抑制后AKT的反馈激活，同时靶向mTORC 1/2可能更有效。在这项研究中，我们研究了双重mTORC 1/2抑制剂OSI-027和阿霉素之间的相互作用，在体外和体内。研究发现，OSI-027可以减少mTORC 1和mTORC 2底物（包括4 E-BP 1、p70 S6 K和AKT（Ser 473））的磷酸化，并抑制HCC细胞增殖。类似于OSI-027处理，mTORC 2的敲低诱导G 0-G1期细胞周期停滞。相比之下，雷帕霉素或敲低mTORC 1增加了AKT（Ser 473）的磷酸化，但几乎没有抗增殖作用。值得注意的是，OSI-027与多柔比星以依赖于HCC细胞中MDR 1表达的方式协同抗增殖功效。在HCC异种移植小鼠模型中也观察到OSI-027和多柔比星的协同抗肿瘤作用。此外，OSI-027诱导的细胞周期停滞和MDR 1下调需要AKT。我们的研究结果为mTORC 1/mTORC 2双重抑制剂（如OSI-027）作为单药治疗或与细胞毒性药物联合治疗HCC提供了依据。Mol Cancer Ther; 14（8）; 1805-15.©2015 AACR.
mTOR is aberrantly activated in hepatocellular carcinoma (HCC) and plays pivotal roles in tumorigenesis and chemoresistance. Rapamycin has been reported to exert antitumor activity in HCC and sensitizes HCC cells to cytotoxic agents. However, due to feedback activation of AKT after mTOR complex 1 (mTORC1) inhibition, simultaneous targeting of mTORC1/2 may be more effective. In this study, we examined the interaction between the dual mTORC1/2 inhibitor OSI-027 and doxorubicin in vitro and in vivo. OSI-027 was found to reduce phosphorylation of both mTORC1 and mTORC2 substrates, including 4E-BP1, p70S6K, and AKT (Ser473), and inhibit HCC cell proliferation. Similar to OSI-027 treatment, knockdown of mTORC2 induced G0–G1 phase cell-cycle arrest. In contrast, rapamycin or knockdown of mTORC1 increased phosphorylation of AKT (Ser473), yet had little antiproliferative effect. Notably, OSI-027 synergized with doxorubicin for the antiproliferative efficacy in a manner dependent of MDR1 expression in HCC cells. The synergistic antitumor effect of OSI-027 and doxorubicin was also observed in a HCC xenograft mouse model. Moreover, AKT was required for OSI-027–induced cell-cycle arrest and downregulation of MDR1. Our findings provide a rationale for dual mTORC1/mTORC2 inhibitors, such as OSI-027, as monotherapy or in combination with cytotoxic agents to treat HCC. Mol Cancer Ther; 14(8); 1805–15. ©2015 AACR.