title: The histone deacetylase inhibitor vorinostat prevents TNFα-induced necroptosis by regulating multiple signaling pathways.
abstract: Histone deacetylase (HDAC) inhibitors are novel anticancer reagents that have recently been reported to have anti-inflammatory and neuroprotective effects; however, the mechanisms underlying their activities are largely undefined. The data from this study show that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) can protect L929 cells from TNFα-induced necroptosis. This effect involves multiple mechanisms, including the upregulation of cFLIPL expression, the enhanced activation of NFκB and p38 MAPK, and the inactivation of JNK. In addition, SAHA could initiate cell autophagy by inhibiting Akt and mTOR, which also play important roles in protecting cells from necroptosis. Because cell necroptosis is important for inflammation-related deterioration and neurodegenerative disease, our results indicate that preventing cell necrosis may be an important mechanism through which HDAC inhibitor compounds exert their anti-inflammatory or neuroprotective effects.
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Cognitive and Mental Health Research Center, #27 Taiping Road, Beijing, 100850, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Cognitive and Mental Health Research Center, #27 Taiping Road, Beijing, 100850, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Cognitive and Mental Health Research Center, #27 Taiping Road, Beijing, 100850, China.
authors.forename: Guozhu
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Cognitive and Mental Health Research Center, #27 Taiping Road, Beijing, 100850, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry, China Medical University, Shenyang, China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Cognitive and Mental Health Research Center, #27 Taiping Road, Beijing, 100850, China.
authors.forename: Song
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Cognitive and Mental Health Research Center, #27 Taiping Road, Beijing, 100850, China.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Cognitive and Mental Health Research Center, #27 Taiping Road, Beijing, 100850, China. yuxd@bmi.ac.cn.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Yu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D009336:Necrosis / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000077337:Vorinostat; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D000077337:Vorinostat; C546843:mTOR protein, mouse; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4