Molecular mechanisms of protein kinase C-induced apoptosis in prostate cancer cells.
Protein kinase C (PKC) isozymes, a family of serine-threonine kinases, are important regulators of cell proliferation and malignant transformation. Phorbol esters, the prototype PKC activators, cause PKC translocation to the plasma membrane in prostate cancer cells, and trigger an apoptotic response. Studies in recent years have determined that each member of the PKC family exerts different effects on apoptotic or survival pathways. PKCdelta, one of the novel PKCs, is a key player of the apoptotic response via the activation of the p38 MAPK pathway. Studies using RNAi revealed that depletion of PKCdelta totally abolishes the apoptotic effect of the phorbol ester PMA. Activation of the classical PKCalpha promotes the dephosphorylation and inactivation of the survival kinase Akt. Studies have assigned a pro-survival role to PKCepsilon, but the function of this PKC isozyme remains controversial. Recently, it has been determined that the PKC apoptotic effect in androgen-dependent prostate cancer cells is mediated by the autocrine secretion of death factors. PKCdelta stimulates the release of TNFalpha from the plasma membrane, and blockade of TNFalpha secretion or TNFalpha receptors abrogates the apoptotic response of PMA. Molecular analysis indicates the requirement of the extrinsic apoptotic cascade via the activation of death receptors and caspase-8. Dissecting the pathways downstream of PKC isozymes represents a major challenge to understanding the molecular basis of phorbol ester-induced apoptosis.
Gonzalez-Guerrico
Anatilde M
AM
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA.
Meshki
John
J
Xiao
Liqing
L
Benavides
Fernando
F
Conti
Claudio J
CJ
Kazanietz
Marcelo G
MG
D000728:Androgens / Q000378:metabolism; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry; D008297:Male; D008957:Models, Genetic; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000737:chemistry; D051745:Protein Kinase C-delta / Q000737:chemistry; D051744:Protein Kinase C-epsilon / Q000737:chemistry; D015398:Signal Transduction
D000728:Androgens; D007527:Isoenzymes; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D053181:Caspase 8