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摘要
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 p21RAS 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 delta isozyme demonstrated that PKC delta 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 delta protein and activity in cells, whereas inhibition of p21RAS activity decreased the expression of the PKC delta protein. Activation of the Akt survival pathway by oncogenic Ras required PKC delta activity. Akt activity was dramatically decreased after PKC delta suppression in cells containing activated p21(RAS). Conversely, constitutively activated Akt rescued cells from apoptosis induced by PKC delta inhibition. Collectively, these findings demonstrate that p21(RAS), through its downstream effector PI3K, induces PKC delta expression and that this increase in PKC delta activity, acting through Akt, is required for cell survival. The p21RAS effector molecule responsible for the initiation of the apoptotic signal after suppression of PKC delta activity was also determined to be PI3K. PI3K (p110(CAAX), where AA is aliphatic amino acid) was sufficient for induction of apoptosis after PKC delta 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 delta and Akt. Selective suppression of PKC delta activity and consequent induction of apoptosis is a potential strategy for targeting of tumor cells containing an activated p21(RAS).
- 出版日期2007-5-4
