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Protein kinase C- regulates resistance to UV- and -irradiation-induced apoptosis in glioblastoma cells by preventing caspase-9 activation

Departments of Pathology (Neuropathology) (I.M.H., J.E.C., G.T.R., S.R.V.), Anesthesiology (J.J.S.), and Neurosurgery (M.E.S.), University of Virginia, Charlottesville, VA 22908

² Address correspondence and reprints requests to Isa M. Hussaini, Dept. of Pathology (Neuropathology), The University of Virginia, Charlottesville, VA 22908.

Both increased cell proliferation and apoptosis play important roles in the malignant growth of glioblastomas. We have demonstrated recently that the differential expression of protein kinase C (PKC)- increases the proliferative capacity of glioblastoma cells in culture; however, specific functions for this novel PKC isozyme in the regulation of apoptosis in these tumors has not been defined. In the present study of several glioblastoma cell lines, we investigated the role of PKC- in preventing UV- and -irradiation-induced apoptosis and in caspase-dependent signaling pathways that mediate cell death. Exposure to UV or irradiation killed 80% to 100% of PKC--deficient nonneoplastic human astrocytes and U-1242 MG cells, but had little effect on the PKC--expressing U-251 MG and U-373 MG cells. PKC- appears to mediate resistance to irradiation specifically such that when PKC-h was stably expressed in U-1242 MG cells, more than 80% of these cells developed resistance to irradiation-induced apoptosis. Reducing PKC- expression by transient and stable expression of antisense PKC- in wild-type U-251 MG cells results in increased sensitivity to UV irradiation in a fashion similar to U-1242 MG cells and nonneoplastic astrocytes. Irradiation of PKC--deficient glioblastoma cells resulted in the activation of caspase-9 and caspase-3, cleavage of poly (ADP-ribose) polymerase (PARP), and a substantial increase in subdiploid DNA content that did not occur in PKC--expressing tumor cells. A specific inhibitor (Ac-DEVD-CHO) of caspase-3 blocked apoptosis in PKC--deficient U-1242 MG cells. The data demonstrate that resistance to UV and irradiation in glioblastoma cell lines is modified significantly by PKC- expression and that PKC- appears to block the apoptotic cascade at caspase-9 activation.

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