对致癌 mTOR 通路的遗传剖析揭示了通过 4EBP-eIF4E 进行药物成瘾的翻译控制。
Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E.
机构信息
School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
出版信息
Cancer Cell. 2010 Mar 16;17(3):249-61. doi: 10.1016/j.ccr.2010.01.021.
We genetically dissect the contribution of the most prominent downstream translational components of mTOR signaling toward Akt-driven lymphomagenesis. While phosphorylation of rpS6 is dispensable for cancer formation, 4EBP-eIF4E exerts significant control over cap-dependent translation, cell growth, cancer initiation, and progression. This effect is mediated at least in part through 4EBP-dependent control of Mcl-1 expression, a key antiapoptotic protein. By using an active site inhibitor of mTOR, PP242, we show a marked therapeutic response in rapamycin-resistant tumors. The therapeutic benefit of PP242 is mediated through inhibition of mTORC1-dependent 4EBP-eIF4E hyperactivation. Thus, the 4EBP-eIF4E axis downstream of mTOR is a druggable mediator of translational control and Akt-mediated tumorigenesis that has important implications for the treatment of human cancers.
我们从遗传学角度剖析了 mTOR 信号最显著的下游翻译成分对 Akt 驱动的淋巴瘤发生的贡献。虽然 rpS6 的磷酸化对于癌症的形成不是必需的，但 4EBP-eIF4E 对帽依赖性翻译、细胞生长、癌症起始和进展具有显著的控制作用。这种作用至少部分是通过 4EBP 依赖性控制 Mcl-1 表达来介导的，Mcl-1 是一种关键的抗凋亡蛋白。通过使用 mTOR 的活性位点抑制剂 PP242，我们在雷帕霉素耐药肿瘤中观察到显著的治疗反应。PP242 的治疗益处是通过抑制 mTORC1 依赖性 4EBP-eIF4E 过度激活来介导的。因此，mTOR 下游的 4EBP-eIF4E 轴是翻译控制和 Akt 介导的肿瘤发生的可用药理性介质，这对人类癌症的治疗具有重要意义。
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