Low-dose 12-O-tetradecanoylphorbol-13-acetate enhances tumor necrosis factor related apoptosis-inducing ligand induced apoptosis in prostate cancer cells.
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Zhang X, Li W, Olumi AF
Low-dose 12-O-tetradecanoylphorbol-13-acetate enhances tumor necrosis factor related apoptosis-inducing ligand induced apoptosis in prostate cancer cells.
Clin Cancer Res. 2007 Dec 1;13(23):7181-90.
- PubMed ID
- 18056199 [ View in PubMed]
- Abstract
PURPOSE: 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. EXPERIMENTAL DESIGN: 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Lexatumumab Tumor necrosis factor receptor superfamily member 10B Protein Humans UnknownNot Available Details