mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation.
mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation.
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癌细胞中的MTORC1抑制在营养限制期间可防止谷氨酰胺溶解介导的凋亡。
DOI：
10.1038/ncomms14124
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发表时间：
2017-01-23
影响因子：
16.6
通讯作者：
Durán RV
中科院分区：
文献类型：
--
作者：
Villar VH;Nguyen TL;Delcroix V;Terés S;Bouchecareilh M;Salin B;Bodineau C;Vacher P;Priault M;Soubeyran P;Durán RV
作为细胞生长的主协调者，mTORC 1被不同的代谢输入激活，特别是谷氨酰胺的代谢（谷氨酰胺分解），以控制广泛的细胞过程，包括自噬。作为一种公认的肿瘤促进剂，mTORC 1抑制剂如雷帕霉素已被批准作为抗癌药物，但其在患者中的总体结果相当差。在这里，我们表明，mTORC1也提出了肿瘤抑制功能的营养限制条件。因此，在营养不平衡期间，mTORC1通过氨解的激活抑制癌细胞中的自噬并诱导细胞凋亡。重要的是，雷帕霉素治疗重新激活自噬并阻止mTORC1介导的细胞凋亡。我们还观察到mTORC 1激活凋亡的能力是由衔接蛋白p62介导的。因此，mTORC1介导的p62在营养失衡期间的上调诱导p62与半胱天冬酶8的结合以及随后的半胱天冬酶途径的激活。我们的数据强调了自噬作为雷帕霉素治疗后的生存机制的作用。mTORC1通路的抑制剂被认为是抗癌药物。在这里，作者表明，在营养限制下，氨解诱导的mTORC1激活通过抑制自噬诱导细胞凋亡，强调在这种条件下mTORC1的抑制导致癌细胞的存活。
A master coordinator of cell growth, mTORC1 is activated by different metabolic inputs, particularly the metabolism of glutamine (glutaminolysis), to control a vast range of cellular processes, including autophagy. As a well-recognized tumour promoter, inhibitors of mTORC1 such as rapamycin have been approved as anti-cancer agents, but their overall outcome in patients is rather poor. Here we show that mTORC1 also presents tumour suppressor features in conditions of nutrient restrictions. Thus, the activation of mTORC1 by glutaminolysis during nutritional imbalance inhibits autophagy and induces apoptosis in cancer cells. Importantly, rapamycin treatment reactivates autophagy and prevents the mTORC1-mediated apoptosis. We also observe that the ability of mTORC1 to activate apoptosis is mediated by the adaptor protein p62. Thus, the mTORC1-mediated upregulation of p62 during nutrient imbalance induces the binding of p62 to caspase 8 and the subsequent activation of the caspase pathway. Our data highlight the role of autophagy as a survival mechanism upon rapamycin treatment. Inhibitors of the mTORC1 pathway are considered anti-cancer drugs. Here, the authors show that on nutrient restriction, glutaminolysis-induced activation of mTORC1 induces apoptosis via inhibiting autophagy, highlighting that under such conditions inhibition of mTORC1 results in survival of cancer cells.