Protein kinase Cα and protein kinase Cδ play opposite roles in the proliferation and apoptosis of glioma cells

Revital Mandil, Ely Ashkenazi, Michal Blass, Ilana Kronfeld, Gila Kazimirsky, Guy Rosenthal, Felix Umansky, Patricia S. Lorenzo, Peter M. Blumberg, Chaya Brodie

Research output: Contribution to journalArticlepeer-review

176 Scopus citations

Abstract

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 PKCα and lower levels of PKCδ as compared with low-grade astrocytomas. Consistent with a mechanistic role for these differences, overexpression of PKCα 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 PKCδ inhibited cell proliferation and enhanced GFAP expression. Using PKC chimeras, we found that the regulatory domains of PKCα and PKCδ mediated their effects on cell proliferation and GFAP expression. PKCα and δ 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 PKCα levels had little effect on apoptosis in response to etoposide. In contrast, overexpression of PKCδ rendered the U87 cells more sensitive to the apoptotic effect of etoposide, and PKCδ was cleaved in these cells by a caspase-dependent process. Furthermore, the glioma cell line U373, which expresses endogenous PKCδ underwent apoptosis in response to etoposide, and the apoptotic response was blocked by the PKCδ inhibitor rottlerin. Our results suggest that PKCα and PKCδ play opposite roles in the proliferation and apoptosis of glioma cells.

Original languageEnglish
Pages (from-to)4612-4619
Number of pages8
JournalCancer Research
Volume61
Issue number11
StatePublished - 1 Jun 2001

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