Exp Mol Med.  2009 May;41(5):362-369. 10.3858/emm.2009.41.5.041.

Tunicamycin enhances TRAIL-induced apoptosis by inhibition of cyclin D1 and the subsequent downregulation of survivin

• Zhang HY
• Du ZX
• Liu BQ
• Gao YY
• Meng X
• Guan Y
• Deng WW
• Wang HQ

• KMID: 1123811
• DOI: http://doi.org/10.3858/emm.2009.41.5.041

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) has been proposed as a promising cancer therapy that preferentially induces apoptosis in cancer cells, but not most normal tissues. However, many cancers are resistant to TRAIL by mechanisms that are poorly understood. In this study, we showed that tunicamycin, a naturally occurring antibiotic, was a potent enhancer of TRAIL-induced apoptosis through downregulation of survivin. The tunicamycin-mediated sensitization to TRAIL was efficiently reduced by forced expression of survivin, suggesting that the sensitization was mediated at least in part through inhibition of survivin expression. Tunicamycin also repressed expression of cyclin D1, a cell cycle regulator commonly overexpressed in thyroid carcinoma. Furthermore, silencing cyclin D1 by RNA interference reduced survivin expression and sensitized thyroid cancer cells to TRAIL; in contrast, forced expression of cyclin D1 attenuated tunicamycin-potentiated TRAIL-induced apoptosis via over-riding downregulation of survivin. Collectively, our results demonstrated that tunicamycin promoted TRAIL-induced apoptosis, at least in part, by inhibiting the expression of cyclin D1 and subsequent survivin. Of note, tunicamycin did not sensitize the differentiated thyroid epithelial cells to TRAIL-induced apoptosis. Thus, combined treatment with tunicamycin and TRAIL may offer an attractive strategy for safely treating resistant thyroid cancers.

Keyword

apoptosis; BIRC5 protein, human; cyclin D1; thyroid neoplasms; TNF-related apoptosis-inducing ligand; tunicamycin

MeSH Terms

Anti-Bacterial Agents/*pharmacology
*Apoptosis
Cell Line, Tumor
Cyclin D1/*antagonists & inhibitors/metabolism
*Down-Regulation
Humans
Microtubule-Associated Proteins/*genetics/metabolism
TNF-Related Apoptosis-Inducing Ligand/*metabolism
Tunicamycin/*pharmacology