The Enigma of Rapamycin Dosage.
The Enigma of Rapamycin Dosage.
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DOI：
10.1158/1535-7163.mct-15-0720
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发表时间：
2016-03
影响因子：
5.7
通讯作者：
Foster DA
中科院分区：
文献类型：
--
作者：
Mukhopadhyay S;Frias MA;Chatterjee A;Yellen P;Foster DA
哺乳动物雷帕霉素靶蛋白（mTOR）通路是细胞生长、增殖、代谢和存活的关键调节因子。在大多数癌症中已经观察到mTOR信号传导的失调，因此，已经广泛研究了mTOR途径用于治疗干预。雷帕霉素是一种高特异性抑制mTOR的天然产物。然而，其功效在几种情况下因剂量而异。首先，需要不同剂量的雷帕霉素来抑制不同细胞系中的mTOR;第二，需要不同剂量的雷帕霉素来抑制不同mTOR底物的磷酸化;第三，两种mTOR复合物mTORC 1和mTORC 2对雷帕霉素的敏感性不同。有趣的是，雷帕霉素剂量的神秘特性在很大程度上可以通过雷帕霉素和磷脂酸（PA）之间对mTOR的竞争来解释。雷帕霉素和PA对mTOR具有相反的作用，由此雷帕霉素使两种mTOR复合物不稳定，PA使两种mTOR复合物稳定。在这篇综述中，我们讨论了雷帕霉素的抗癌治疗的背景下剂量的属性。
The mammalian target of rapamycin (mTOR) pathway is a critical regulator of cell growth, proliferation, metabolism and survival. Dysregulation of mTOR signaling has been observed in most cancers and thus, the mTOR pathway has been extensively studied for therapeutic intervention. Rapamycin is a natural product that inhibits mTOR with high specificity. However, its efficacy varies by dose in several contexts. First, different doses of rapamycin are needed to suppress mTOR in different cell lines; second, different doses of rapamycin are needed to suppress the phosphorylation of different mTOR substrates; and third, there is a differential sensitivity of the two mTOR complexes mTORC1 and mTORC2 to rapamycin. Intriguingly, the enigmatic properties of rapamycin dosage can be explained in large part by the competition between rapamycin and phosphatidic acid (PA) for mTOR. Rapamycin and PA have opposite effects on mTOR whereby rapamycin destabilizes and PA stabilizes both mTOR complexes. In this review, we discuss the properties of rapamycin dosage in the context of anti-cancer therapeutics.