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Protein Kinase C and Protein Kinase C Play Opposite Roles in the Proliferation and Apoptosis of Glioma Cells¹

Faculty of Life-Sciences, Bar-Ilan University, Ramat-Gan, Israel 52900 [R. M., M. B., I. K., G. K., C. B.]; Department of Neurosurgery, Hadassa Medical Center, Jerusalem, Israel [E. A., G. R., F. U.]; and Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, NIH, Bethesda, Maryland 20892 [P. S. L., P. M. B.]

Protein kinase C (PKC) has been implicated in the proliferation and apoptosis of glial tumors, but the role of specific PKC isoforms remains unresolved. Comparing brain tumors differing in degree of malignancy, we found that malignant gliomas expressed higher levels of PKC and lower levels of PKC as compared with low-grade astrocytomas. Consistent with a mechanistic role for these differences, overexpression of PKC in the human U87 glioma cell line resulted in enhanced cell proliferation and decreased glial fibrillary acidic protein (GFAP) expression as compared with controls. Reciprocally, overexpression of PKC inhibited cell proliferation and enhanced GFAP expression. Using PKC chimeras, we found that the regulatory domains of PKC and PKC mediated their effects on cell proliferation and GFAP expression. PKC and have been implicated as potential signaling molecules in apoptosis. Therefore, we examined the role of these isoforms in the resistance of glioma cells to apoptotic stimuli. In U87 cells, manipulation of PKC levels had little effect on apoptosis in response to etoposide. In contrast, overexpression of PKC rendered the U87 cells more sensitive to the apoptotic effect of etoposide, and PKC was cleaved in these cells by a caspase-dependent process. Furthermore, the glioma cell line U373, which expresses endogenous PKC, underwent apoptosis in response to etoposide, and the apoptotic response was blocked by the PKC inhibitor rottlerin. Our results suggest that PKC and PKC play opposite roles in the proliferation and apoptosis of glioma cells.

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