PMID- 31723016 OWN - NLM STAT- MEDLINE DCOM- 20201020 LR - 20240229 IS - 1535-9484 (Electronic) IS - 1535-9476 (Print) IS - 1535-9476 (Linking) VI - 19 IP - 1 DP - 2020 Jan TI - Mitochondrial Oxidative Phosphorylation Complex Regulates NLRP3 Inflammasome Activation and Predicts Patient Survival in Nasopharyngeal Carcinoma. PG - 142-154 LID - S1535-9476(20)30011-6 [pii] LID - 10.1074/mcp.RA119.001808 [doi] AB - We previously reported that tumor inflammasomes play a key role in tumor control and act as favorable prognostic markers in nasopharyngeal carcinoma (NPC). Activated inflammasomes frequently form distinguishable specks and govern the cellular secretion of IL-1beta. However, we know little about the biological and biochemical differences between cells with and without apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation. In this study, we used proteomic iTRAQ analysis to analyze the proteomes of NPC cells that differ in their ASC speck formation upon cisplatin treatment. We identified proteins that were differentially over-expressed in cells with specks, and found that they fell into two Gene ontology (GO) pathways: mitochondrial oxidative phosphorylation (OxPhos) and ubiquinone metabolism. We observed up-regulation of various components of the OxPhos machinery (including NDUFB3, NDUFB8 and ATP5B), and subsequently found that these changes lead to mitochondrial ROS (mtROS) production, which promotes the formation and activation of NLRP3 inflammasomes and subsequent pyroptosis. In NPC patients, better local recurrence-free survival was significantly associated with high-level expression of NDUFB8 (p = 0.037) and ATP5B (p = 0.029), as examined using immunohistochemistry. However, there were no significant associations between the expression of NDUFB8 and ATP5B with overall survival of NPC patients. Together, our results demonstrate that up-regulated mitochondrial OxPhos components are strongly associated with NLRP3 inflammasome activation in NPC. Our findings further suggest that high-level expression of OxPhos components could be markers for local recurrence and/or promising therapeutic targets in patients with NPC. CI - (c) 2020 Chung et al. FAU - Chung, I-Che AU - Chung IC AD - Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan. FAU - Chen, Lih-Chyang AU - Chen LC AD - Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan. FAU - Tsang, Ngan-Ming AU - Tsang NM AD - Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; Department of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan. FAU - Chuang, Wen-Yu AU - Chuang WY AD - Department of Pathology, Chang Gung Memorial Hospital, Linkou, and Chang Gung University College of Medicine, Taoyuan, Taiwan. FAU - Liao, Tzu-Chieh AU - Liao TC AD - Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan. FAU - Yuan, Sheng-Ning AU - Yuan SN AD - Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan. FAU - OuYang, Chun-Nan AU - OuYang CN AD - Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan. FAU - Ojcius, David M AU - Ojcius DM AD - Department of Biomedical Sciences, University of the Pacific, San Francisco, California 94103; Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan. FAU - Wu, Chih-Ching AU - Wu CC AD - Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan; Department of Otolaryngology - Head & Neck Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan. Electronic address: luckywu@mail.cgu.edu.tw. FAU - Chang, Yu-Sun AU - Chang YS AD - Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; Department of Otolaryngology - Head & Neck Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan. Electronic address: ysc@mail.cgu.edu.tw. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191113 PL - United States TA - Mol Cell Proteomics JT - Molecular & cellular proteomics : MCP JID - 101125647 RN - 0 (ATP5F1B protein, human) RN - 0 (Biomarkers, Tumor) RN - 0 (Inflammasomes) RN - 0 (NDUFB8 protein, human) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (NLRP3 protein, human) RN - 0 (Reactive Oxygen Species) RN - EC 3.6.3.- (Mitochondrial Proton-Translocating ATPases) RN - EC 7.1.1.2 (Electron Transport Complex I) SB - IM MH - Adult MH - Aged MH - Biomarkers, Tumor/genetics/metabolism MH - Cell Line, Tumor MH - Disease-Free Survival MH - Electron Transport Complex I/genetics/*metabolism MH - Female MH - Follow-Up Studies MH - Humans MH - Inflammasomes/*metabolism MH - Male MH - Middle Aged MH - Mitochondria/*metabolism MH - Mitochondrial Proton-Translocating ATPases/genetics/*metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism MH - Nasopharyngeal Carcinoma/*metabolism/mortality/pathology MH - Nasopharyngeal Neoplasms/*metabolism/mortality/pathology MH - Oxidative Phosphorylation MH - Proteomics/methods MH - RNA Interference MH - Reactive Oxygen Species/metabolism MH - Up-Regulation/genetics PMC - PMC6944234 OTO - NOTNLM OT - cancer biology OT - iTRAQ OT - inflammatory response OT - mitochondria function or biology OT - nasopharyngeal carcinoma OT - oxidative stress COIS- The authors declare that they have no conflicts of interest with the contents of this article. EDAT- 2019/11/15 06:00 MHDA- 2020/10/21 06:00 PMCR- 2021/01/01 CRDT- 2019/11/15 06:00 PHST- 2019/10/05 00:00 [received] PHST- 2019/11/01 00:00 [revised] PHST- 2019/11/15 06:00 [pubmed] PHST- 2020/10/21 06:00 [medline] PHST- 2019/11/15 06:00 [entrez] PHST- 2021/01/01 00:00 [pmc-release] AID - S1535-9476(20)30011-6 [pii] AID - RA119.001808 [pii] AID - 10.1074/mcp.RA119.001808 [doi] PST - ppublish SO - Mol Cell Proteomics. 2020 Jan;19(1):142-154. doi: 10.1074/mcp.RA119.001808. Epub 2019 Nov 13.