Abstract
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. 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. 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. 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.
Highlights
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-FLICE – like inhibitory protein (c-FLIP)(L)
Because we have found that the activation of c-Fos/AP-1 is necessary for cancer cells to undergo TRAIL-induced apoptosis and TPA is a strong inducer of c-Fos/AP-1, we hypothesized that TPA might sensitize TRAIL-resistant prostate cancer cells to undergo apoptosis after TRAIL treatment
PC3 prostate cancer cells are sensitive to TRAIL-induced apoptosis, LNCaP cells and nontumorigenic and immortalized BPH-1 cells are resistant to the proapoptotic effects of TRAIL (Fig. 1A)
Summary
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). Results: We show that the combination of TRAIL with low-doseTPA has no effect on nonmalignant prostate epithelial cells; 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. Conclusions: TPA, when combined with the proapoptotic agent TRAIL, is effective in changing the phenotype of someTRAIL-resistant prostate cancer cells to aTRAIL-sensitive phenotype. We have found that c-Fos/AP-1 functions as a proapoptotic molecule by directly repressing the antiapoptotic gene, c-FLIP(L) This finding suggests that strategies to potentiate c-Fos/AP-1 activation and/or inhibit c-FLIP(L) may enhance the efficacy of TRAIL for treatment of various malignancies. TPA has the potential of enhancing the therapeutic effects of some systemic agents for the treatment of various malignancies
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