Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
Oncogene. 2014 Apr 3;33(14):1776-87. doi: 10.1038/onc.2013.139. Epub 2013 Apr 22.
Nutrient stress that produces quiescence and catabolism in normal cells is lethal to cancer cells, because oncogenic mutations constitutively drive anabolism. One driver of biosynthesis in cancer cells is the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Activating mTORC1 by deleting its negative regulator tuberous sclerosis complex 2 (TSC2) leads to hypersensitivity to glucose deprivation. We have previously shown that ceramide kills cells in part by triggering nutrient transporter loss and restricting access to extracellular amino acids and glucose, suggesting that TSC2-deficient cells would be hypersensitive to ceramide. However, murine embryonic fibroblasts (MEFs) lacking TSC2 were highly resistant to ceramide-induced death. Consistent with the observation that ceramide limits access to both amino acids and glucose, TSC2(-/-) MEFs also had a survival advantage when extracellular amino acids and glucose were both reduced. As TSC2(-/-) MEFs were resistant to nutrient stress despite sustained mTORC1 activity, we assessed whether mTORC1 signaling might be beneficial under these conditions. In low amino acid and glucose medium, and following ceramide-induced nutrient transporter loss, elevated mTORC1 activity significantly enhanced the adaptive upregulation of new transporter proteins for amino acids and glucose. Strikingly, the introduction of oncogenic Ras abrogated the survival advantage of TSC2(-/-) MEFs upon ceramide treatment most likely by increasing nutrient demand. These results suggest that, in the absence of oncogene-driven biosynthetic demand, mTORC1-dependent translation facilitates the adaptive cellular response to nutrient stress.
营养压力会导致正常细胞进入静止和分解代谢状态，从而对癌细胞产生致命影响，因为致癌突变会持续驱动合成代谢。癌细胞中生物合成的一个驱动因素是哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）信号复合物。通过删除其负调节剂结节性硬化复合物 2（TSC2）来激活 mTORC1，会导致对葡萄糖剥夺的过度敏感。我们之前曾表明，神经酰胺通过触发营养转运体的损失并限制细胞外氨基酸和葡萄糖的摄取，从而杀死细胞，这表明 TSC2 缺陷细胞会对神经酰胺过度敏感。然而，缺乏 TSC2 的鼠胚胎成纤维细胞（MEFs）对神经酰胺诱导的死亡具有高度抗性。与神经酰胺限制氨基酸和葡萄糖摄取的观察结果一致，当细胞外氨基酸和葡萄糖都减少时，TSC2(-/-) MEFs 也具有生存优势。由于 TSC2(-/-) MEFs 尽管持续存在 mTORC1 活性，但仍能抵抗营养应激，因此我们评估了在这些条件下 mTORC1 信号是否有益。在低氨基酸和葡萄糖培养基中，并且在神经酰胺诱导的营养转运体损失之后，升高的 mTORC1 活性显著增强了新的氨基酸和葡萄糖转运蛋白的适应性上调。引人注目的是，致癌性 Ras 的引入在神经酰胺处理后消除了 TSC2(-/-) MEFs 的生存优势，这很可能是通过增加营养需求来实现的。这些结果表明，在没有致癌基因驱动的生物合成需求的情况下，mTORC1 依赖性翻译促进了细胞对营养应激的适应性反应。
