Tunicamycin enhances human colon cancer cells to TRAIL-induced apoptosis by JNK-CHOP-mediated DR5 upregulation and the inhibition of the EGFR pathway.
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively induces apoptosis in many tumor cells while leaving normal cells intact and is thus an attractive candidate for antitumor therapies. This paper reports that the combination of tunicamycin plus TRAIL produced a strong synergistic effect in TRAIL-sensitive human colon cancer HCT116 cells and TRAIL-resistant HT-29 cells. On a cellular mechanistic level, tunicamycin-enhanced TRAIL-induced apoptosis by death receptor (DR) 5 upregulation and DR4 deglycosylation. Knockdown of DR5 but not DR4 expression by specific shRNAs or siRNAs significantly increased tunicamycin-mediated and TRAIL-mediated cell viability. DR5 induction was regulated by C/EBP homologous protein (CHOP) and JNK as CHOP siRNA or JNK inhibitor SP600125 considerably abolished the DR5 induction. In addition, tunicamycin inhibited epidermal growth factor receptor glycosylation and the downstream signaling pathways, Akt and extracellular signal-regulated kinases activation, which might also be required for TRAIL sensitization by tunicamycin. In summary, tunicamycin effectively enhanced TRAIL-induced apoptosis might through JNK-CHOP-mediated DR5 upregulation and the inhibition of the epidermal growth factor receptor pathway.
aJilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University bDepartment of Radiology, The Second Part of the First Hospital, Jilin University, Changchun, People's Republic of China.
Xiaoqing
X
Guo
Yue
Y
Meng
Xiaotong
X
Sheng
Yuan
Y
Guan
Fenglei
F
Zhang
Zhen
Z
Han
Yuying
Y
Kang
Guihua
G
Tai
Yifa
Y
Zhou
Hairong
H
Cheng
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D014415:Tunicamycin / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
C497249:DDIT3 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014415:Tunicamycin; D051742:Transcription Factor CHOP; C512478:EGFR protein, human; D066246:ErbB Receptors