title: Tumor suppressor BLU promotes TRAIL-induced apoptosis by downregulating NF-κB signaling in nasopharyngeal carcinoma.
abstract: 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.
authors.affiliation: Department 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.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department 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.
authors.forename: Zunnan
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department 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.
authors.forename: Ziyou
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department 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.
authors.forename: Shumin
authors.initials: S
authors.lastname: Liu
authors.affiliation: Center for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Alf
authors.initials: A
authors.lastname: Grandien
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingemar
authors.initials: I
authors.lastname: Ernberg
authors.affiliation: Department 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.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: He
authors.affiliation: Department 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.
authors.forename: Xiangning
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D003598:Cytoskeletal Proteins; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; D025521:Tumor Suppressor Proteins; C472720:ZMYND10 protein, human; D011065:Poly(ADP-ribose) Polymerases; D053181:Caspase 8
keywords: BLU/ZMYND10; NF-κB; TRAIL; nasopharyngeal carcinoma; tumor suppressor gene