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Insulin-like Growth Factor I-mediated Protection from Rapamycin-induced Apoptosis Is Independent of Ras-Erk1-Erk2 and Phosphatidylinositol 3'-Kinase-Akt Signaling Pathways¹

Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105-2794

The mTOR inhibitor rapamycin induces G₁ cell cycle accumulation and p53-independent apoptosis of the human rhabdomyosarcoma cell line Rh1. Insulin-like growth factor I (IGF-I) and insulin, but not epidermal growth factor or platelet-derived growth factor, completely prevented apoptosis of this cell line. Because the Ras-Erk1-Erk2 and phosphatidylinositol 3'-kinase (PI3K)-Akt pathways are implicated in the survival of various cancer cells, we determined whether protection from rapamycin-induced apoptosis by IGF-I requires one or both of these pathways. Despite the blocking of Ras-Erk signaling by the addition of PD 98059 (a MEK1 inhibitor) or by the overexpression of dominant-negative RasN17, IGF-I completely prevented rapamycin-induced death. Inhibition of Ras signaling did not prevent Akt activation by IGF-I. To determine the role of the PI3K-Akt pathway in rescuing cells from apoptosis caused by rapamycin, cells expressing dominant-negative Akt were tested. This mutant protein inhibited IGF-I-induced phosphorylation of Akt and blocked phosphorylation of glycogen synthase kinase 3. The prevention of rapamycin-induced apoptosis by IGF-I was not inhibited by expression of dominant-negative Akt either alone or under conditions in which LY 294002 inhibited PI3K signaling. Furthermore, IGF-I prevented rapamycin-induced apoptosis when the Ras-Erk1-Erk2 and PI3K-Akt pathways were blocked simultaneously. Similar experiments in a second rhabdomyosarcoma cell line, Rh30, using pharmacological inhibitors of PI3K or MEK1, alone or in combination, failed to block IGF-I rescue from rapamycin-induced apoptosis. Therefore, we conclude that a novel pathway(s) is responsible for the IGF-I-mediated protection against rapamycin-induced apoptosis in these rhabdomyosarcoma cells.

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