Low-dose 12-O-tetradecanoylphorbol-13-acetate enhances tumor necrosis factor related apoptosis-inducing ligand induced apoptosis in prostate cancer cells.
OBJECTIVE
Previously, we have shown that c-Fos/activator protein-1 (AP-1) promotes tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by repressing the antiapoptotic molecule c-FLIP(L). In this study, we investigated whether synthetic induction of c-Fos/AP-1 by 12-O-tetradecanoylphorbol-13-acetate (TPA) converts the phenotype of TRAIL-resistant prostate cancer cells to a TRAIL-sensitive phenotype in vitro and in vivo.


METHODS
Low-dose TPA was used to determine whether LNCaP prostate cancer cells could be converted to a TRAIL-sensitive phenotype in in vitro and in vivo studies. We also assessed whether TPA enhancement of TRAIL-induced apoptosis varies between androgen-sensitive and androgen-insensitive prostate cancer cells and evaluated the role of TRAIL receptors, DR4 and DR5, in TPA-enhanced TRAIL-induced apoptosis.


RESULTS
We show that the combination of TRAIL with low-dose TPA has no effect on nonmalignant prostate epithelial cells; however, TPA up-regulates most AP-1 proteins and AP-1 activity, reduces c-FLIP(L), and potentiates TRAIL-induced apoptosis. We show that the combination of TPA + TRAIL is effective in promoting apoptosis in both hormone-sensitive LNCaP and hormone-insensitive LNCaP-C4-2 prostate cancer cells. Although TPA enhances the TRAIL-receptor 1 (DR4) level, sensitization of prostate cancer cells seems to be more dependent on TRAIL-receptor 2 (DR5) than TRAIL-receptor 1 levels. In vivo xenograft experiments suggest that TPA elevates the expression of c-Fos and reduces c-FLIP(L). Combination of TPA with TRAIL-receptor 2 agonist antibody, lexatumumab, effectively increases apoptosis and reduces LNCaP xenograft tumor burden.


CONCLUSIONS
TPA, when combined with the proapoptotic agent TRAIL, is effective in changing the phenotype of some TRAIL-resistant prostate cancer cells to a TRAIL-sensitive phenotype.
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Xiaoping
X
Zhang
Wenhua
W
Li
Aria F
AF
Olumi
D000728:Androgens / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000737:chemistry / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D000728:Androgens; D000911:Antibodies, Monoclonal; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D018808:Transcription Factor AP-1; C510234:lexatumumab; D013755:Tetradecanoylphorbol Acetate