Protein kinase Cepsilon interacts with Bax and promotes survival of human prostate cancer cells.
Prostatic glandular epithelial cells express protein kinase Cepsilon (PKCepsilon ), an oncoprotein that coordinately disrupts the reactivation of the tumor suppressor Rb, derepressess transcriptional elongation of the c-myc oncogene, and propagates survival signals in LNCaP cells. Since the activation of such a program may contribute to the progression of human prostate cancer, a proteomic analysis was performed to gain a more global perspective on the signaling network that PKCepsilon might be capable of engaging in prostate cancer cells. Using CWR22 xenografts, we identified at least 18 different structural, signaling, and stress-related proteins that associated with PKCepsilon, including an interaction with the proapoptotic protein Bax that was novel to recurrent CWR22 tumors. An investigation into the biological significance of the PKCepsilon association with Bax provided the first evidence of an inverse relationship between endogenous levels of PKCepsilon and susceptibility of prostate cancer cells to the apoptotic effects of phorbol esters. Western blot and antisense experiments demonstrated that CWR-R1 cells expressed moderate levels of PKCepsilon and relied on this protein to survive in the presence of phorbol esters, while the apoptosis normally induced by phorbol esters in PKCepsilon -deficient LNCaP cells was dependent on the presence of Bax. Forced expression of PKCepsilon in LNCaP cells was sufficient to confer a significant resistance to phorbol esters and this resistance was associated with an inhibition of phorbol ester-induced Bax conformational rearrangements that are important for Bax oligomerization, mitochondrial integration, and cytochrome c release. Considered in their entirety, our data suggest that an association of PKCepsilon with Bax may neutralize apoptotic signals propagated through a mitochondrial death-signaling pathway.
McJilton
Meagan A
MA
Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA.
Van Sikes
C
C
Wescott
Ginger G
GG
Wu
Daqing
D
Foreman
Tonia L
TL
Gregory
Christopher W
CW
Weidner
Douglas A
DA
Harris Ford
O
O
Morgan Lasater
A
A
Mohler
James L
JL
Terrian
David M
DM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003574:Cytochrome c Group / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D003574:Cytochrome c Group; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D013755:Tetradecanoylphorbol Acetate