Targeting mTOR signaling for cancer therapy
Targeting mTOR signaling for cancer therapy
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DOI：
10.1016/s1471-4892(03)00071-7
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发表时间：
2003-08-01
影响因子：
4
通讯作者：
Houghton, PJ
中科院分区：
文献类型：
--
作者：
Huang, S;Houghton, PJ
哺乳动物雷帕霉素靶蛋白（mTOR）是一种非典型的丝氨酸/苏氨酸激酶，在细胞增殖、生长、分化、迁移和存活的调控中起重要作用。mTOR信号传导的失调发生在不同的人类肿瘤中，并且可以赋予对mTOR抑制剂的更高易感性。雷帕霉素及其衍生物CCI-779和RAD 001（命名为雷帕霉素）特异性抑制mTOR的功能，导致核糖体S6 K1失活，并通过4 E-BP 1/eIF 4 E途径抑制帽依赖性翻译起始。总体效应是细胞在细胞周期的G1期的积累和潜在的凋亡。临床前研究表明，雷帕霉素是培养物中许多肿瘤细胞系和鼠同基因肿瘤模型或人异种移植物增殖的有效抑制剂。RAD 001和CCI-779分别作为抗癌药物处于I期和II期试验中。这些试验已经证明了CCI-779有希望的抗癌活性和相对轻微的副作用。新出现的结果表明，抑制mTOR信号传导可以作为一种潜在的肿瘤选择性治疗策略。
The mammalian target of rapamycin (mTOR), an atypical serine/threonine kinase, plays a central role in the regulation of cell proliferation, growth, differentiation, migration and survival. Dysregulation of mTOR signaling occurs in diverse human tumours, and can confer higher susceptibility to inhibitors of mTOR. Rapamycin and its derivatives, CCI-779 and RAD001 (designated rapamycins), specifically inhibit the function of mTOR, leading to inactivation of ribosomal S6K1 and inhibition of cap-dependent translation initiation through the 4E-BP1/eIF4E pathway. The overall effect is an accumulation of cells in the G1 phase of the cell-cycle, and potential apoptosis. Preclinical studies indicate that rapamycins are potent inhibitors of the proliferation of numerous tumour cell lines in culture and of murine syngeneic tumour models or human xenografts. RAD001 and CCI-779 are in phase I and II trials, respectively, as anti-cancer agents. These trials have demonstrated promising anti-cancer activity and relatively mild side effects of CCI-779. Emerging results suggest that inhibition of mTOR signaling can be exploited as a potential tumour-selective therapeutic strategy.