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The Phosphatidylinositide 3'-Kinase/Akt Survival Pathway Is a Target for the Anticancer and Radiosensitizing Agent PKC412, an Inhibitor of Protein Kinase C¹

Department of Radiation Oncology, University Hospital Zurich, CH-8091 Zurich [A. T., D. Z., S. R., C. G., S. B., M. P.]; Novartis Pharma, Inc., Department of Oncology Research, CH-4002 Basel [D. F.]; Friedrich Miescher Institute, CH-4058 Basel [B. H.]; and Department of Applied Biosciences, ETH-Zurich, CH-8092 Zurich [A. T., D. Z., A. S.], Switzerland

Activation of the phosphatidylinositol 3'-kinase (PI3K)/Akt survival pathway protects against apoptotic stress stimuli. Therefore, compounds that down-regulate this pathway are of clinical interest for single and combined anticancer treatment modalities. Here we demonstrate that the cytotoxic effect of the protein kinase C (PKC)-inhibitor N-benzoylated staurosporine (PKC412) is mediated via the PI3K/Akt pathway. Dose-dependent down-regulation of the proliferative activity, activation of the apoptotic machinery, and cell killing by PKC412 (0–1 µM) in Rat1a-fibroblasts and H-ras-oncogene-transformed fibroblasts correlated with a decrease of Akt phosphorylation and a reduced phosphorylation of the endogenous Akt-substrate GSK3-. Expression of the dominant-active myristoylated form of Akt abrogated this cytotoxic effect of PKC412. Experiments with Apaf-1-deficient cells revealed that PKC412-induced cytotoxicity depends on an intact apoptosome but that the decrease of Akt phosphorylation is not attributable to apoptosis execution. Comparative experiments indicate that PKC412 and the parent-compound staurosporine down-regulate this survival pathway upstream or at the level of Akt but by a different mechanism than the PI3K-inhibitor LY294002. Furthermore, inhibition of this pathway by PKC412 is relevant for sensitization to ionizing radiation. These results demonstrate the specific role of this signaling pathway for the PKC412-mediated down-regulation of an apoptotic threshold and its cytotoxicity.

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