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Protein Kinase C Overexpression Enhances Radiation Sensitivity via Extracellular Regulated Protein Kinase 1/2 Activation, Abolishing the Radiation-induced G₂-M Arrest¹

Laboratory of Radiation Effect, Korea Cancer Center Hospital, Seoul 139-706, Korea [Y-J. L., C-K. C., T-H. K, S-J. L., Y-S. L.]; Division of Molecular Life Sciences, Ewha Womans University, Seoul 120-750, Korea [Y-J. L.]; Department of Molecular Pharmacology, ISIS Pharmaceuticals, Carlsbad, California 92008 [N. M. D]; and Department of Biochemistry and Molecular Biophysics and Herbert Comprehensive Cancer Center, Columbia University, New York, New York 10032 [J-W. S]

Protein kinase C (PKC) has been widely implicated in regulation ofcell growth/cell cycle progression and apoptosis. However,the role of PKC in radiosensitivity and cell cycle regulation remains unclear. Overexpression of PKC increased Ca²⁺-independent PKC activity without altering other PKC isoforms (PKC, -ß1, -, and -), and extracellular regulated protein kinase (ERK) 1/2 activity was also increased in PKC-specific manner. A clonogenic survival assay showed that PKC-overexpressed cells had more radiosensitivity and pronounced induction of apoptosis than control cells. Flow cytometric analysis revealed that PKC made the cells escape from radiation-induced G₂-M arrest. Moreover, p53 and p21^Waf induction by radiation were higher in PKC-overexpressed cells than control cells, and PKC-mediated apoptosis was reduced, when radiation-induced ERK1/2 activity was inhibited by PD98059. Furthermore, PKC antisense and rottlerin, PKC inhibitor-abrogated PKC-mediated radiosensitivity and reduced ERK1/2 activity to the control vector level. These results demonstrated that PKC overexpression enhanced radiation-induced apoptosis and radiosensitivity via ERK1/2 activation, thereby abolishing the radiation-induced G₂-M arrest and finally apoptosis.

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