The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1.
The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1.
复制标题
MTORC1抑制了细胞外蛋白作为养分的利用。
DOI：
10.1016/j.cell.2015.06.017
复制
发表时间：
2015-07-16
期刊：
影响因子：
64.5
通讯作者：
Thompson CB
中科院分区：
文献类型：
--
作者：
Palm W;Park Y;Wright K;Pavlova NN;Tuveson DA;Thompson CB
尽管被各种营养物质包围，哺乳动物细胞优先代谢葡萄糖和游离氨基酸。最近，Ras诱导的细胞外蛋白的巨胞饮作用被证明可以减少转化细胞对细胞外谷氨酰胺的依赖。在这里，我们表明，蛋白质巨胞饮也可以作为一种必需氨基酸的来源。细胞外蛋白的溶酶体降解可以维持细胞存活并诱导mTORC 1的激活，但不能引起显著的细胞蓄积。与其在氨基酸充足条件下的生长促进活性不同，我们发现当细胞依赖于细胞外蛋白作为氨基酸来源时，mTORC 1激活抑制增殖。抑制mTORC1导致内吞蛋白质的catalysts增加，并在体外营养缺乏条件下和体内血管受损肿瘤内增强细胞增殖。因此，通过阻止细胞外蛋白的营养消耗，mTORC 1将生长与游离氨基酸的可用性结合起来。这些结果可能对使用mTOR抑制剂作为治疗剂具有重要意义。
Despite being surrounded by diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids. Recently, Ras-induced macropinocytosis of extracellular proteins was shown to reduce a transformed cell’s dependence on extracellular glutamine. Here, we demonstrate that protein macropinocytosis can also serve as an essential amino acid source. Lysosomal degradation of extracellular proteins can sustain cell survival and induce activation of mTORC1, but fails to elicit significant cell accumulation. Unlike its growth-promoting activity under amino acid-replete conditions, we discovered that mTORC1 activation suppresses proliferation when cells rely on extracellular proteins as an amino acid source. Inhibiting mTORC1 results in increased catabolism of endocytosed proteins and enhances cell proliferation during nutrient-depleted conditions in vitro and within vascularly compromised tumors in vivo. Thus, by preventing nutritional consumption of extracellular proteins, mTORC1 couples growth to availability of free amino acids. These results may have important implications for the use of mTOR inhibitors as therapeutics.