Department of Pharmacology and Oncology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4764-9. doi: 10.1073/pnas.0910872107. Epub 2010 Feb 22.
Mammalian target of rapamycin (mTOR) constitutes a nodal point of a signaling network that regulates cell growth and proliferation in response to various environmental cues ranging from growth factor stimulation to nutrients to stress. Whether mTOR is also affected by cholesterol homeostasis, however, has remained unknown. We report that blockade of cholesterol trafficking through lysosome by a newly identified inhibitor of angiogenesis, itraconazole, leads to inhibition of mTOR activity in endothelial cells. Inhibition of mTOR by itraconazole but not rapamycin can be partially restored by extracellular cholesterol delivered by cyclodextrin. Moreover, other known inhibitors of endosomal/lysosomal cholesterol trafficking as well as siRNA knockdown of Niemann-Pick disease type C (NPC) 1 and NPC2 also cause inhibition of mTOR in endothelial cells. In addition, both the accumulation of cholesterol in the lysosome and inhibition of mTOR caused by itraconazole can be reversed by thapsigarin. These observations suggest that mTOR is likely to be involved in sensing membrane sterol concentrations in endothelial cells, and the cholesterol trafficking pathway is a promising target for the discovery of inhibitors of angiogenesis.
哺乳动物雷帕霉素靶蛋白（mTOR）是一个信号网络的节点，该网络可响应各种环境信号（从生长因子刺激到营养物质再到应激）调节细胞生长和增殖。然而，mTOR 是否也受胆固醇稳态的影响尚不清楚。我们报告称，通过新鉴定的血管生成抑制剂伊曲康唑阻断溶酶体中的胆固醇转运，可导致内皮细胞中 mTOR 活性的抑制。伊曲康唑而非雷帕霉素抑制 mTOR 可部分被 cyclodextrin 递送的细胞外胆固醇恢复。此外，其他已知的内体/溶酶体胆固醇转运抑制剂以及 NPC1 和 NPC2 的 siRNA 敲低也可导致内皮细胞中 mTOR 的抑制。此外，伊曲康唑引起的溶酶体胆固醇积累和 mTOR 抑制均可被黄皮酰胺逆转。这些观察结果表明，mTOR 可能参与感受内皮细胞中膜甾醇浓度，胆固醇转运途径可能是发现血管生成抑制剂的有希望的靶点。
