Overexpression of PKCepsilon sensitizes LNCaP human prostate cancer cells to induction of apoptosis by bryostatin 1.
Phorbol 12-myristate 13-acetate (PMA)-induced apoptosis of androgen sensitive LNCaP human prostate cancer cells is a well known phenomenon that involves prolonged translocation of multiple protein kinase C (PKC) isozymes to nonnuclear membranes. We have shown recently that PMA-induced death of C4-2 cells, androgen hypersensitive derivatives of LNCaP cells, requires both PKCdelta and a redundant pathway that includes PKCs alpha and epsilon. In contrast, it has been reported that overexpression of murine PKCepsilon in LNCaP cells renders those cells resistant to PMA-induced death, as well as androgen insensitive. Here we report that inducible or constitutive overexpression of human PKCepsilon does not alter the sensitivity of LNCaP cells to either PMA or androgen, nor does it alter expression of caveolin-1 or phosphorylated Rb, reported effects of overexpression of murine PKCepsilon. Moreover, overexpression of very high amounts of PKCepsilon sensitized LNCaP cells to induction of apoptosis by bryostatin 1, a non tumor-promoting activator and down-regulator of PKC isozymes that blocks PMA-induced apoptosis of parental LNCaP cells, mimicked our previous results with overexpression of PKCalpha in LNCaP cells. Given reports that overexpression of PKCepsilon is frequent in human prostate tumors, our results may have important implications for a potential prostate cancer therapy.
Powell
C Thomas
CT
Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. powellt@ccf.org
Yin
Lihong
L
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D054713:Bryostatins; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015151:Immunoblotting; D018942:Macrolides / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection
D000970:Antineoplastic Agents; D054713:Bryostatins; D018942:Macrolides; D016160:Retinoblastoma Protein; D013196:Dihydrotestosterone; C046785:bryostatin 1; C016658:phorbolol myristate acetate; D051744:Protein Kinase C-epsilon; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate