Tunicamycin enhances TRAIL-induced apoptosis by inhibition of cyclin D1 and the subsequent downregulation of survivin.
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.
Zhang
Hai-Yan
HY
Department of Geriatrics, China Medical University, Shenyang, China. zhy_doctor@hotmail.com
Du
Zhen-Xian
ZX
Liu
Bao-Qin
BQ
Gao
Yan-Yan
YY
Meng
Xin
X
Guan
Yifu
Y
Deng
Wei-Wei
WW
Wang
Hua-Qin
HQ
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; D014415:Tunicamycin; D019938:Cyclin D1