title: Protein kinase Calpha and protein kinase Cdelta play opposite roles in the proliferation and apoptosis of glioma cells.
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 PKCalpha and lower levels of PKCdelta as compared with low-grade astrocytomas. Consistent with a mechanistic role for these differences, overexpression of PKCalpha 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 PKCdelta inhibited cell proliferation and enhanced GFAP expression. Using PKC chimeras, we found that the regulatory domains of PKCalpha and PKCdelta mediated their effects on cell proliferation and GFAP expression. PKCalpha and delta 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 PKCalpha levels had little effect on apoptosis in response to etoposide. In contrast, overexpression of PKCdelta rendered the U87 cells more sensitive to the apoptotic effect of etoposide, and PKCdelta was cleaved in these cells by a caspase-dependent process. Furthermore, the glioma cell line U373, which expresses endogenous PKCdelta, underwent apoptosis in response to etoposide, and the apoptotic response was blocked by the PKCdelta inhibitor rottlerin. Our results suggest that PKCalpha and PKCdelta play opposite roles in the proliferation and apoptosis of glioma cells.
authors.affiliation: Faculty of Life-Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Mandil
authors.forename: E
authors.initials: E
authors.lastname: Ashkenazi
authors.forename: M
authors.initials: M
authors.lastname: Blass
authors.forename: I
authors.initials: I
authors.lastname: Kronfeld
authors.forename: G
authors.initials: G
authors.lastname: Kazimirsky
authors.forename: G
authors.initials: G
authors.lastname: Rosenthal
authors.forename: F
authors.initials: F
authors.lastname: Umansky
authors.forename: P S
authors.initials: PS
authors.lastname: Lorenzo
authors.forename: P M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: C
authors.initials: C
authors.lastname: Brodie
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001254:Astrocytoma / Q000201:enzymology* / Q000473:pathology; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D005909:Glioblastoma / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D011493:Protein Kinase C / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005904:Glial Fibrillary Acidic Protein; D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; D005047:Etoposide; C496628:PRKCA protein, human; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D020169:Caspases