miR-133a Promotes TRAIL Resistance in Glioblastoma via Suppressing Death Receptor 5 and Activating NF-κB Signaling

• Published in: Molecular therapy. Nucleic acids Vol. 8; pp. 482 - 492
• Main Authors: Wang, Shan-shan, Feng, Lu, Hu, Bao-guang, Lu, Ying-fei, Wang, Wei-mao, Guo, Wei, Suen, Chun-wai, Jiao, Bao-hua, Pang, Jian-xin, Fu, Wei-ming, Zhang, Jin-fang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.09.2017; Elsevier Limited; American Society of Gene & Cell Therapy; Elsevier
• Subjects: Apoptosis; Binding sites; Brain cancer; Cancer therapies; Clinical trials; Conflicts of interest; Death receptors; DR5; Drug resistance; Gene expression; Glioblastoma; glioblastoma multiforme; Laboratory animals; Ligands; microRNA-133; MicroRNAs; NF-κB protein; NF-κB signaling; Original; Statistical analysis; TRAIL; TRAIL protein; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumors; microRNA-133; NF-κB signaling; glioblastoma multiforme; TRAIL; DR5
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2017.07.015

Recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), as a novel cancer therapeutic, is being tested in phase II and III clinical trials; however, TRAIL resistance remains a big obstacle preventing its clinical application. Considering that TRAIL-induced apoptosis through death receptors DR4 and DR5, their activation may be an alternative pathway to suppress TRAIL resistance. In this study, a negative correlation between DR5 expression and TRAIL resistance was observed, and miR-133a was predicted to be the most promising candidate to suppress DR5 expression. Further investigation demonstrated that miR-133a knockdown dramatically suppressed TRAIL resistance in glioblastoma in vitro and in vivo. An NF-κB family member, phosphorylated IκBα (P-IκBα), was shown to be stimulated by miR-133a, leading to the activation of this signaling. Finally, miR-133a was found to be inversely correlated with DR5 expression in human clinical specimens. In conclusion, our data demonstrate that miR-133a promotes TRAIL resistance in glioblastoma by suppressing DR5 expression and activating NF-κB signaling.