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J. Biol. Chem., Vol. 282, Issue 18, 13199-13210, May 4, 2007

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Protein Kinase C Is Required for Survival of Cells Expressing Activated p21^RAS*

From the Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts 02118

Inhibition of protein kinase C (PKC) activity in transformed cells and tumor cells containing activated p21^RAS results in apoptosis. To investigate the pro-apoptotic pathway induced by the p21^RAS oncoprotein, we first identified the specific PKC isozyme necessary to prevent apoptosis in the presence of activated p21^RAS. Dominant-negative mutants of PKC, short interfering RNA vectors, and PKC isozyme-specific chemical inhibitors directed against the PKC isozyme demonstrated that PKC plays a critical role in p21^RAS-mediated apoptosis. An activating p21^RAS mutation, or activation of the phosphatidylinositol 3-kinase (PI3K) Ras effector pathway, increased the levels of PKC protein and activity in cells, whereas inhibition of p21^RAS activity decreased the expression of the PKC protein. Activation of the Akt survival pathway by oncogenic Ras required PKC activity. Akt activity was dramatically decreased after PKC suppression in cells containing activated p21^RAS. Conversely, constitutively activated Akt rescued cells from apoptosis induced by PKC inhibition. Collectively, these findings demonstrate that p21^RAS, through its downstream effector PI3K, induces PKC expression and that this increase in PKC activity, acting through Akt, is required for cell survival. The p21^RAS effector molecule responsible for the initiation of the apoptotic signal after suppression of PKC activity was also determined to be PI3K. PI3K (p110^CAAX, where AA is aliphatic amino acid) was sufficient for induction of apoptosis after PKC inhibition. Thus, the same p21^RAS effector, PI3K, is responsible for delivering both a pro-apoptotic signal and a survival signal, the latter being mediated by PKC and Akt. Selective suppression of PKC activity and consequent induction of apoptosis is a potential strategy for targeting of tumor cells containing an activated p21^RAS.

Received for publication, November 1, 2006 , and in revised form, March 8, 2007.

^* This work was supported by the Philip Morris External Research Program, NCI Grants CA108100 and CA112102 from the National Institutes of Health, a Littlefield-AACR Grant in Metastatic Colon Cancer Research, and the Karin Grunebaum Cancer Research Foundation (to D. V. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Cancer Research Center, K-701, 715 Albany St., Boston, MA 02118. Tel.: 617-638-4173; Fax: 617-638-4176; E-mail: dfaller{at}bu.edu.

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