Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
Department of Pathology, University Health Network, Toronto, Ontario, Canada.
Mol Cancer Res. 2018 Apr;16(4):682-695. doi: 10.1158/1541-7786.MCR-17-0696. Epub 2018 Feb 16.
The mTOR signaling pathway is a central regulator of protein synthesis and cellular metabolism in response to the availability of energy, nutrients, oxygen, and growth factors. mTOR activation leads to phosphorylation of multiple downstream targets including the eukaryotic initiation factor 4E (eIF4E) binding proteins-1 and -2 (EIF4EBP1/4E-BP1 and EIF4EBP2/4E-BP2). These binding proteins inhibit protein synthesis, but are inactivated by mTOR to stimulate cell growth and metabolism. However, the role of these proteins in the context of aberrant activation of mTOR, which occurs frequently in cancers through loss of PTEN or mutational activation of the PI3K/AKT pathway, is unclear. Here, even under conditions of aberrant mTOR activation, hypoxia causes dephosphorylation of 4E-BP1/4E-BP2 and increases their association with eIF4E to suppress translation. This is essential for hypoxia tolerance as knockdown of 4E-BP1 and 4E-BP2 decreases proliferation under hypoxia and increases hypoxia-induced cell death. In addition, genetic deletion of 4E-BP1 and 4E-BP2 significantly accelerates all phases of cancer development in the context of PTEN loss-driven prostate cancer in mice despite potent PI3K/AKT and mTOR activation. However, even with a more rapid onset, tumors that establish in the absence of 4E-BP1 and 4E-BP2 have reduced levels of tumor hypoxia and show increased cell death within hypoxic tumor regions. Together, these data demonstrate that 4E-BP1 and 4E-BP2 act as essential metabolic breaks even in the context of aberrant mTOR activation and that they are essential for the creation of hypoxia-tolerant cells in prostate cancer. .
mTOR 信号通路是一种中央调节蛋白合成和细胞代谢的反应，以适应能量、营养、氧气和生长因子的可用性。mTOR 的激活导致多个下游靶标的磷酸化，包括真核起始因子 4E(eIF4E)结合蛋白-1 和 -2(EIF4EBP1/4E-BP1 和 EIF4EBP2/4E-BP2)。这些结合蛋白抑制蛋白质合成，但被 mTOR 失活以刺激细胞生长和代谢。然而，在 mTOR 异常激活的情况下，这些蛋白质的作用尚不清楚，mTOR 异常激活经常发生在癌症中，通过 PTEN 缺失或 PI3K/AKT 通路的突变激活。在这里，即使在异常 mTOR 激活的情况下，缺氧也会导致 4E-BP1/4E-BP2 的去磷酸化，并增加它们与 eIF4E 的结合，以抑制翻译。这对于缺氧耐受性是必不可少的，因为 4E-BP1 和 4E-BP2 的敲低会减少缺氧下的增殖，并增加缺氧诱导的细胞死亡。此外，在小鼠中，PTEN 缺失驱动的前列腺癌中，即使存在强烈的 PI3K/AKT 和 mTOR 激活，4E-BP1 和 4E-BP2 的基因缺失也会显著加速癌症发展的所有阶段。然而，即使发病更快，在缺乏 4E-BP1 和 4E-BP2 的情况下建立的肿瘤，其肿瘤缺氧水平降低，并显示出缺氧肿瘤区域内细胞死亡增加。总之，这些数据表明，即使在异常 mTOR 激活的情况下，4E-BP1 和 4E-BP2 也作为必需的代谢阻断剂发挥作用，并且对于前列腺癌中创建耐受缺氧的细胞是必不可少的。
