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

Abstract

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.

Dexmedetomidine Enhances Autophagy via α2-AR/AMPK/mTOR Pathway to Inhibit the Activation of NLRP3 Inflammasome and Subsequently Alleviates Lipopolysaccharide-Induced Acute Kidney Injury

“…Other previous studies indicated that mitochondrial dysfunction also plays a vital role in NLRP3 inflammasome activation. Both mitochondrial reactive oxygen species and membrane proteins are involved in activation of the NLRP3 inflammasome (Kim et al, 2018b;Chung et al, 2019). In our study, we observed that NLRP3 localized with TOM20, a mitochondrial protein, as well as ultrastructural damage in mitochondria.…”

Prognostic Value of Inflammasomes in Head and Neck Carcinoma: A Meta-analysis

“…As in ammatory storms may promote the carcinogenesis (32,33), they may have relationships with cancer formation. In recent years, in ammasomes have been reported with higher or lower levels in HNCs, especially NLRP3 (20,21,23,(29)(30)(31) and AIM2 (22)(23)(24). However, no agreement has been reached on the relationships between in ammasomes and the prognosis of HNC.…”

“…Among them, in ammasomes are also linked with head and neck cancers. However, although it is reported that some in ammasomes were upregulated in certain kinds of head and neck cancers (20), indicating a poorer prognosis (21), some were unchanged (22) and others even were favorable prognostic markers (23,24). They may have contradictory functions in promoting antitumor immuno-microenvironment and triggering oncogenic activities (23).…”

Detection of In Vivo Inflammasome Activation for Predicting Sepsis Mortality

“…The in vivo ASC-speck formation within blood leukocytes is a distinguishing feature of inflammasome formation and permits a direct and quantitative study of blood samples by flow cytometry. This assay was well validated ( 30 – 32 ) and has been implemented previously ( 33 , 34 ).…”