Mitochondrial Oxidative Phosphorylation Complex Regulates NLRP3 Inflammasome Activation and Predicts Patient Survival in Nasopharyngeal Carcinoma.

Journal Article (Journal Article)

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-1β. 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.

Full Text

Duke Authors

Cited Authors

  • Chung, I-C; Chen, L-C; Tsang, N-M; Chuang, W-Y; Liao, T-C; Yuan, S-N; OuYang, C-N; Ojcius, DM; Wu, C-C; Chang, Y-S

Published Date

  • January 2020

Published In

Volume / Issue

  • 19 / 1

Start / End Page

  • 142 - 154

PubMed ID

  • 31723016

Pubmed Central ID

  • PMC6944234

Electronic International Standard Serial Number (EISSN)

  • 1535-9484

International Standard Serial Number (ISSN)

  • 1535-9476

Digital Object Identifier (DOI)

  • 10.1074/mcp.ra119.001808

Language

  • eng