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.