Protein kinase C-ε regulates the apoptosis and survival of glioma cells

Hana Okhrimenko, Wei Lu, Cunli Xiang, Nathan Hamburger, Gila Kazimirsky, Chaya Brodie

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97 Scopus citations

Abstract

In this study, we examined the role of protein kinase C (PKC)-ε in the apoptosis and survival of glioma cells using tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-stimulated cells and silencing of PKCε expression. Treatment of glioma cells with TRAIL induced activation, caspase-dependent cleavage, and down-regulation of PKCε within 3 to 5 hours of treatment. Overexpression of PKCε inhibited the apoptosis induced by TRAIL, acting downstream of caspase 8 and upstream of Bid cleavage and cytochrome c release from the mitochondria. A caspase-resistant PKCε mutant (D383A) was more protective than PKCε, suggesting that both the cleavage of PKCε and its down-regulation contributed to the apoptotic effect of TRAIL. To further study the role of PKCε in glioma cell apoptosis, we employed short interfering RNAs directed against the mRNA of PKCε and found that silencing of PKCε expression induced apoptosis of various glioma cell lines and primary glioma cultures. To delineate the molecular mechanisms involved in the apoptosis induced by silencing of PKCε, we examined the expression and phosphorylation of various apoptosis-related proteins. We found that knockdown of PKCε did not affect the expression of Bcl2 and Bax or the phosphorylation and expression of Erk1/2, c-Jun-NH2-kinase, p38, or STAT, whereas it selectively reduced the expression of AKT. Similarly, TRAIL reduced the expression of AKT in glioma cells and this decrease was abolished in cells overexpressing PKCε. Our results suggest that the cleavage of PKCε and its down-regulation play important roles in the apoptotic effect of TRAIL. Moreover, PKCε regulates AKT expression and is essential for the survival of glioma cells.

Original languageEnglish
Pages (from-to)7301-7309
Number of pages9
JournalCancer Research
Volume65
Issue number16
DOIs
StatePublished - 15 Aug 2005

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