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Protein Kinase C- Regulates the Apoptosis and Survival of Glioma Cells

¹ Gonda (Goldschmied) Medical Diagnosis Research Center, Faculty of Life-Sciences, Bar-Ilan University, Ramat Gan, Israel and ² The Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan

Requests for reprints: Chaya Brodie, The Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI 48202. Phone: 313-916-8619; Fax: 313-916-9855; E-mail: chaya{at}mail.biu.ac.il.

In this study, we examined the role of protein kinase C (PKC)- in the apoptosis and survival of glioma cells using tumor necrosis factor–related apoptosis inducing ligand (TRAIL)-stimulated cells and silencing of PKC expression. Treatment of glioma cells with TRAIL induced activation, caspase-dependent cleavage, and down-regulation of PKC within 3 to 5 hours of treatment. Overexpression of PKC 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 PKC mutant (D383A) was more protective than PKC, suggesting that both the cleavage of PKC and its down-regulation contributed to the apoptotic effect of TRAIL. To further study the role of PKC in glioma cell apoptosis, we employed short interfering RNAs directed against the mRNA of PKC and found that silencing of PKC 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 PKC, we examined the expression and phosphorylation of various apoptosis-related proteins. We found that knockdown of PKC 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 PKC. Our results suggest that the cleavage of PKC and its down-regulation play important roles in the apoptotic effect of TRAIL. Moreover, PKC regulates AKT expression and is essential for the survival of glioma cells.

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