Perifosine inhibits mammalian target of rapamycin signaling through facilitating degradation of major components in the mTOR axis and induces autophagy.
Perifosine inhibits mammalian target of rapamycin signaling through facilitating degradation of major components in the mTOR axis and induces autophagy.
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DOI：
10.1158/0008-5472.can-09-2190
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发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Sun SY
中科院分区：
文献类型：
--
作者：
Fu L;Kim YA;Wang X;Wu X;Yue P;Lonial S;Khuri FR;Sun SY
Perifosine是一种具有抗肿瘤活性的烷基磷脂，已在临床前研究和临床试验中得到证实。这种活性部分与其抑制Akt活性的能力有关。研究表明，mTOR轴在调节细胞增殖和存活中起着关键作用，主要通过Akt的下游和上游发挥作用。目前的研究揭示了一种新的机制，通过该机制酪氨酸抑制Akt和mTOR轴。除了抑制Akt外，perifosine还抑制mTOR/raptor和mTOR/rictor复合物的组装。引人注目的是，perifosine通过GSK3/ fbxw7依赖机制促进mTOR轴上Akt和其他主要成分（包括mTOR、raptor、rictor、p70S6K和4E-BP-1）的降解，从而降低了mTOR轴上Akt和其他主要成分的水平。因此，这些结果表明，与经典mTOR抑制剂（如雷帕霉素）抑制mTOR信号传导不同，perifosine通过不同的机制抑制mTOR轴。此外，除了增加PARP的切割外，perifosine还显著增加了II型LC3的水平，这是自噬的标志，这表明perifosine诱导细胞凋亡和自噬。perifosine与一种溶酶体抑制剂联合使用可增强裸小鼠的细胞凋亡并抑制异种移植物的生长，这表明perifosine诱导的自噬可以保护细胞免于凋亡。综上所述，我们得出的结论是，perifosine抑制mTOR信号传导并诱导自噬，突出了perifosine抗癌活性的新机制，以及通过阻止自噬来增强perifosine抗癌功效的潜在策略。
Perifosine is an alkylphospholipid exhibiting antitumor activity as demonstrated in both preclinical studies and clinical trials. This activity is partly associated with its ability to inhibit Akt activity. It has been shown that the mTOR axis plays a critical role in regulation of cell proliferation and survival, primarily through functioning both downstream and upstream of Akt. The current study reveals a novel mechanism by which perifosine inhibits Akt and the mTOR axis. In addition to inhibition of Akt, perifosine inhibited the assembly of both mTOR/raptor and mTOR/rictor complexes. Strikingly, perifosine reduced the levels of Akt and other major components including mTOR, raptor, rictor, p70S6K, and 4E-BP-1 in the mTOR axis by promoting their degradation through a GSK3/FBXW7-dependent mechanism. These results thus suggest that perifosine inhibits the mTOR axis through a different mechanism from inhibition of mTOR signaling by classical mTOR inhibitors such as rapamycin. Moreover, perifosine substantially increased the levels of type II LC3, a hallmark of autophagy, in addition to increasing PARP cleavage, suggesting that perifosine induces both apoptosis and autophagy. The combination of perifosine with a lysosomal inhibitor enhanced apoptosis and inhibited the growth of xenografts in nude mice, suggesting that perifosine-induced autophagy protects cells from undergoing apoptosis. Collectively, we conclude that perifosine inhibits mTOR signaling and induces autophagy, highlighting a novel mechanism accounting for perifosine’s anticancer activity and a potential strategy to enhance perifosine’s anticancer efficacy by preventing autophagy.