Tunicamycin Enhances Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis in Human Prostate Cancer Cells

Abstract

Death receptor 5 (DR5/TRAIL-R2) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L). In this study, we showed that tunicamycin, a naturally occurring antibiotic, is a potent enhancer of TRAIL-induced apoptosis through upregulation of DR5 expression. Tunicamycin significantly sensitized PC-3, androgen-independent human prostate cancer cells, to TRAIL-induced apoptosis. The tunicamycinmediated enhancement of TRAIL-induced apoptosis was markedly blocked by a recombinant human DR5/Fc chimeric protein. Tunicamycin and TRAIL cooperatively activated caspase-8, -10, -9, and -3 and Bid cleavage and this activation was also blocked in the presence of the DR5/Fc chimera. Tunicamycin up-regulated DR5 expression at the mRNA and protein levels in a dose-dependent manner. Furthermore, the tunicamycin-mediated sensitization to TRAIL was efficiently reduced by DR5 small interfering RNA, suggesting that the sensitization was mediated through induction of DR5 expression. Tunicamycin increased DR5 promoter activity and this enhanced activity was diminished by mutation of a CHOPbinding site. In addition, suppression of CHOP expression by small interfering RNA reduced the tunicamycin-mediated induction of DR5. Of note, tunicamycin-mediated induction of CHOP and DR5 protein expression was not observed in normal human peripheral blood mononuclear cells. Moreover, tunicamycin did not sensitize the cells to TRAIL-induced apoptosis. Thus, combined treatment with tunicamycin and TRAIL may be a promising candidate for prostate cancer therapy. (Cancer Res 2005; 65(14): 6364-70)

Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

“…3A), suggesting that Wit A modulates DR5 expression at the transcriptional level. Recently, CHOP was shown to be involved in MG132-or tunicamycin-mediated DR5 upregulation, contributing to the sensitization of TRAIL-mediated apoptosis [14,15]. We found that the protein level of CHOP was significantly increased by Wit A treatment in a dose-dependent manner, but KDEL (Lys-Asp-Glu-Leu), an ER stress marker protein, was not altered (Fig.…”

Inostamycin enhanced TRAIL-induced apoptosis through DR5 upregulation on the cell surface

“…In a previous study, various small molecule compounds, such as tunicamycin, 14 were reported to transactivate the DR5 gene by the upregulation of CHOP. The inostamycin-induced increase in DR5 mRNA was suppressed in CHOP-knockdown HCT116 cells; however, DR5 protein expression was not suppressed.…”

“…Because of the limitations of TRAIL-induced cytotoxicity, the combination of TRAIL with other small molecule compounds has been postulated as strategy to potentiate the cytotoxicity of TRAIL and its therapeutic applications. Indeed, it was reported that several chemotherapeutic agents and natural products, such as CDDP, 10 etoposide, 10,11 doxorubicin, 12 PS-341 (bortezomib), 13 tunicamycin, 14 rottlerin, 15 brandisianins, 16 silibinin 17 and sodium butyrate, 18 were succeeded to cause the sensitization of TRAIL-resistant tumor cells to TRAIL-induced apoptosis.…”

15-deoxy-Δ12,14-prostaglandin J2 up-regulates death receptor 5 gene expression in HCT116 cells: involvement of reactive oxygen species and C/EBP homologous transcription factor gene transcription

“…Although studies have suggested that PRK-like ER kinase/eukaryotic translation initiation factor 2a/ATF4 signaling is more important than ATF6 in inducing CHOP, maximal induction of CHOP in the presence of both ATFs is required (19). Evidence indicates that activation of a CHOP-binding site on the DR5 promoter region accounts for DR5 gene transcription induced by MG132 (14), TM (20), and TG (9). 15dPGJ 2 is not only an endogenous agonist of PPAR-g (21) but also an ER stress inducer (22).…”