Up-regulation of death receptor 4 and 5 by celastrol enhances the anti-cancer activity of TRAIL/Apo-2L.
Our previous study demonstrated that celastrol combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L) exhibited significant synergistic anti-cancer activities, thus we were promoted to investigate the molecular mechanism of this synergy. Here in this study, we show that celastrol up-regulates death receptor 4 (DR4) and 5 (DR5) expression at mRNA, total protein and cell surface levels, and the specific knockdown using DR4- or DR5-targeting siRNA transfection attenuates the PARP cleavage caused by the combination of celastrol and TRAIL/Apo-2L, denoting the critical roles of DR induction in this sensitization. Of note is that although celastrol activates p38 mitogen activated protein kinases (p38 MAPK), SB203580, one specific inhibitor of p38, fails to interrupt celastrol-induced DR4 expression and the enhanced apoptosis caused by celastrol plus TRAIL/Apo-2L. In addition, the protein expression of Mcl-1 and FLIP, two critical antiapoptotic factors, is not decreased upon celastrol treatment under our experimental conditions. Taken together, the present study demonstrates that the enhanced mRNA and protein expression of DR4 and DR5 play prominent roles in the sensitization of celastrol to TRAIL/Apo-2L-induced apoptosis, in a p38 MAPK-independent manner.
Zhu
Hong
H
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Liu
Xiao-Wen
XW
Ding
Wan-Jing
WJ
Xu
Dan-Qing
DQ
Zhao
Yu-Chen
YC
Lu
Wei
W
He
Qiao-Jun
QJ
Yang
Bo
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053978:Pentacyclic Triterpenes; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014162:Transfection; D014315:Triterpenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D053978:Pentacyclic Triterpenes; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D014315:Triterpenes; C050414:celastrol