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.