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Perifosine Inhibits Mammalian Target of Rapamycin Signaling through Facilitating Degradation of Major Components in the mTOR Axis and Induces Autophagy

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia

Requests for reprints: Shi-Yong Sun, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road Northeast, C3088, Atlanta, GA 30322. Phone: 404-778-2170; Fax: 404-778-5520; E-mail: ssun{at}emory.edu.

Perifosine is an alkylphospholipid exhibiting antitumor activity as shown 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 mammalian target of rapamycin (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, 70-kDa ribosomal S6 kinase, and 4E-binding protein 1 in the mTOR axis by promoting their degradation through a GSK3/FBW7-dependent mechanism. These results thus suggest that perifosine inhibits the mTOR axis through a different mechanism from inhibition of mTOR signaling by classic mTOR inhibitors such as rapamycin. Moreover, perifosine substantially increased the levels of type II light chain 3, a hallmark of autophagy, in addition to increasing poly(ADP-ribose) polymerase 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 the anticancer activity of perifosine and a potential strategy to enhance the anticancer efficacy of perifosine by preventing autophagy. [Cancer Res 2009;69(23):8967–76]

Key Words: perifosine • Akt • mTOR • degradation • autophagy • lung cancer cells

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