Protein kinase Cε interacts with Bax and promotes survival of human prostate cancer cells

• Published in: Oncogene Vol. 22; no. 39; pp. 6014 - 6024
• Main Authors: MCJILTON, Meagan A, VAN SIKES, C, TERRIAN, David M, WESCOTT, Ginger G, DAQING WU, FOREMAN, Tonia L, GREGORY, Christopher W, WEIDNER, Douglas A, FORD, O. Harris, LASATER, A. Morgan, MOHLER, James L
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 11-09-2003; Nature Publishing Group
• Subjects: Bax protein; Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Fundamental and applied biological sciences. Psychology; Gynecology. Andrology. Obstetrics; Male genital diseases; Medical sciences; Molecular and cellular biology; Nephrology. Urinary tract diseases; Protein kinase C^e; proteomics; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Human; Bcl-2; Protein kinase C; LNCaP; Prostate disease; Enzyme; phorbol ester; Transferases; CWR22; recurrent prostate cancer; Malignant tumor; Gene expression; Survival; Signal transduction; Proteomics; Apoptosis; Urinary system disease; Recurrent; Carcinogenesis; Protein kinase; Male genital diseases; Prostate cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206795

Prostatic glandular epithelial cells express protein kinase C epsilon (PKC epsilon ), 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 PKC epsilon 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 PKC epsilon , including an interaction with the proapoptotic protein Bax that was novel to recurrent CWR22 tumors. An investigation into the biological significance of the PKC epsilon association with Bax provided the first evidence of an inverse relationship between endogenous levels of PKC epsilon 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 PKC epsilon and relied on this protein to survive in the presence of phorbol esters, while the apoptosis normally induced by phorbol esters in PKC epsilon -deficient LNCaP cells was dependent on the presence of Bax. Forced expression of PKC epsilon 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 PKC epsilon with Bax may neutralize apoptotic signals propagated through a mitochondrial death-signaling pathway.