Tumor suppressor BLU promotes TRAIL-induced apoptosis by downregulating NF-κB signaling in nasopharyngeal carcinoma
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Jiahui Zhou1, Zunnan Huang1, Ziyou Wang1, Shumin Liu1, Alf Grandien3, Ingemar Ernberg2, Zhiwei He1 and Xiangning Zhang1
1Department of Pathophysiology and China-America Cancer Research Institute, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, Guangdong, China
2Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
3Center for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Zunnan Huang, email: [email protected]
Zhiwei He, email: [email protected]
Xiangning Zhang, email: [email protected]
Keywords: nasopharyngeal carcinoma, tumor suppressor gene, BLU/ZMYND10, TRAIL, NF-κB
Received: September 14, 2016 Accepted: November 19, 2016 Published: December 23, 2016
A putative tumor suppressor BLU mapped on the chromosomal 3p21 region, is frequently lost in human tumors including nasopharyngeal carcinoma (NPC). To explore the underlying mechanism of tumor suppression by BLU, its potential to promote apoptosis induced by TRAIL, an effector molecule elaborated by natural killer-T (NKT) cells was investigated. BLU was re-expressed in NPC-derived HNE1 cells by recombinant adenoviral infection and the cells were challenged with recombinant TRAIL. The growth inhibition of BLU was assayed and apoptosis was examined by flow cytometry-based tetramethylrhodamine ethyl ester (TMRE) and annexin V staining, cleavage of pro-caspase-8 and poly ADP ribose polymerase (PARP). The modulation of NF-κB pathway by BLU was evaluated by the reporter activity and estimation of the level of the molecules involved such as IKKalpha, p65 NF-κB, as well as NF-κB induced anti-apoptotic factors cFLIPL and cIAP2. The expression of BLU exerted in vitro and in vivo growth inhibitory effect and promoted TRAIL-induced apoptosis. This phenomenon was validated by FACS-based assays of mitochondrial membrane potential (BLU vs. Vector 87.8% ± 7.7% and 72.1%±6.7% at 6h exposure to TRAIL) and phosphatidylserine turnover (BLU vs. vector: 28.7%±2.9% and 22.6%±2.5%), as well as, enhanced caspapse-8 cleavage. Similar with the findings that BLU promotes chemotherapeutic agent-induced apoptosis, it also augmented death receptor-induced pathway through NF-κB pathway inhibition. In conclusion, BLU suppressed tumor formation by strengthening the antitumor immunity.
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