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PMID: 16103081 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Cancer research ·Vol. 65 ·No. 16 ·2005-08-15 ·Pages 7301-9

Okhrimenko H, Lu W, Xiang C, Hamburger N, Kazimirsky G, Brodie C

Abstract

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

MeSH Terms
Amino Acid Sequence Apoptosis/drug effects,physiology Apoptosis Regulatory Proteins Caspases/metabolism Cell Line, Tumor Down-Regulation Enzyme Activation/drug effects Gene Silencing Glioma/enzymology,genetics,pathology Humans Membrane Glycoproteins/pharmacology Molecular Sequence Data Protein Kinase C/antagonists & inhibitors,biosynthesis,genetics,physiology Protein Kinase C-epsilon Protein Serine-Threonine Kinases/antagonists & inhibitors,biosynthesis Proto-Oncogene Proteins/antagonists & inhibitors,biosynthesis Proto-Oncogene Proteins c-akt RNA, Messenger/antagonists & inhibitors,genetics RNA, Small Interfering/genetics TNF-Related Apoptosis-Inducing Ligand Transfection Tumor Necrosis Factor-alpha/pharmacology
Chemicals
Apoptosis Regulatory Proteins Membrane Glycoproteins Proto-Oncogene Proteins RNA, Messenger RNA, Small Interfering TNF-Related Apoptosis-Inducing Ligand TNFSF10 protein, human Tumor Necrosis Factor-alpha AKT1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt PRKCE protein, human Protein Kinase C Protein Kinase C-epsilon Caspases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Okhrimenko Hana
Gonda (Goldschmied) Medical Diagnosis Research Center, Faculty of Life-Sciences, Bar-Ilan University, Ramat Gan, Israel.
Lu Wei
Xiang Cunli
Hamburger Nathan
Kazimirsky Gila
Brodie Chaya
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-05-1064
Published
2005-08-15
Pages
7301-9
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC1360842
Subset
IM
Grants
NCI NIH HHS · R01 CA109196 · United States
NCI NIH HHS · R01 CA109196-01A1 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-05-1064 PMC Full Text View journal details
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