title: Neoalbaconol induces cell death through necroptosis by regulating RIPK-dependent autocrine TNFα and ROS production.
abstract: Necroptosis/regulated necrosis is a caspase-independent, but receptor interacting protein kinase (RIPK)-dependent form of cell death. In previous studies, neoalbaconol (NA), a constituent extracted from Albatrellus confluens, was demonstrated to induce necroptosis in some cancer cell lines. The molecular mechanism of NA-induced necroptosis is described in this research study. We determined that NA-induced cell death is partly dependent on tumor necrosis factor α (TNFα) feed-forward signaling. More importantly, NA abolished the ubiquitination of RIPK1 by down-regulating E3 ubiquitin ligases, cellular inhibitors of apoptosis protein 1/2 (cIAP1/2) and TNFα receptor-associated factors (TRAFs). The suppression of RIPK1 ubiquitination induced the activation of the non-canonical nuclear factor-κB (NF-κB) pathway and stimulated the transcription of TNFα. Moreover, we also found that NA caused RIPK3-mediated reactive oxygen species (ROS) production and contribution to cell death. Taken together, these results suggested that two distinct mechanisms are involved in NA-induced necroptosis and include RIPK1/NF-κB-dependent expression of TNFα and RIPK3-dependent generation of ROS.
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China.|Key Laboratory of Chinese Ministry of Education, Central South University, Hunan, China.|Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Central South University, Hunan, China.
authors.forename: Xinfang
authors.initials: X
authors.lastname: Yu
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China.|Key Laboratory of Chinese Ministry of Education, Central South University, Hunan, China.|Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Central South University, Hunan, China.
authors.forename: Qipan
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China.|Key Laboratory of Chinese Ministry of Education, Central South University, Hunan, China.|Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Central South University, Hunan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China.|Key Laboratory of Chinese Ministry of Education, Central South University, Hunan, China.|Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Central South University, Hunan, China.
authors.forename: Lanbo
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China.|Key Laboratory of Chinese Ministry of Education, Central South University, Hunan, China.|Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Central South University, Hunan, China.
authors.forename: Xiangjian
authors.initials: X
authors.lastname: Luo
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China.|Key Laboratory of Chinese Ministry of Education, Central South University, Hunan, China.|Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Central South University, Hunan, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China.|Key Laboratory of Chinese Ministry of Education, Central South University, Hunan, China.|Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Central South University, Hunan, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China.|Key Laboratory of Chinese Ministry of Education, Central South University, Hunan, China.|Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Central South University, Hunan, China.
authors.forename: Songling
authors.initials: S
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Feng
authors.affiliation: Liver Cancer Institute, Liver Surgery Department, Zhongshan Hospital.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Liver Cancer Institute, Liver Surgery Department, Zhongshan Hospital.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan, China.
authors.forename: Jikai
authors.initials: J
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China.|Key Laboratory of Chinese Ministry of Education, Central South University, Hunan, China.|Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Central South University, Hunan, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001487:Basidiomycota / Q000737:chemistry; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; C586893:neoalbaconol; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases