Investigation of the Role of Mitochondria in Nlrp3 Inflammasome Formation and Activation in Nasopharyngeal Carcinoma( I )

Inflammation is a hallmark of multiple diseases, especially in the infection-associated cancer. IL-ip, a major proinflammatory cytokine, is regulated by inflammasome in response to pathogen and damage signals. Nasopharyngeal carcinoma (NPC) is a cancer prominent in Taiwanese population and is closely associated with Epstein-Barr virus (EBV) infection. We have examined the inflammasome activation in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) tissues. We found that protein components in three inflammasomes, namely NLPR3, AIM2 and RIG-I, are overexpressed in tumor cells and significantly correlated with better survival of NPC patients after treatment. Upon stimulation, pattern recognition receptors NLPR3, AIM2 and RIG-I will be recruited to ASC, a key platform protein for inflammasome activation, resulting in formation of a protein complex or speck-like particles triggering caspase 1 activation. Activated caspase 1 cleaves pre-IL-ip into a mature form IL-ip and then secreted from the cell. Since approximately 30% of cells that can form activated inflammasomes or speck-like particles upon stimulation, we analyzed protein profiles in cells with or without specks upon stimulation by proteomic (iTRAQ) analysis. We discovered that proteins that are differentially over-presented in cells with specks fall into two GeneGO pathways, oxidative phosphorylation and ubiquinone metabolism, suggesting that mitochondria is a major organelle participated in NLRP3 inflammasome activation. These mitochondria-related genes are also highly expressed in NPC tumor and NPC-HK1 cells (a cell model for inflammasome activation) (preliminary data). In this proposal, we ask fundamental and key questions linking mitochondria and NLRP3 inflammasome activation in NPC. The questions are (1) whether mitochondria are required for NLRP3 inflammasome activation in NPC, and (2) whether mitochondria-induced NLRP3 inflammasome activation associated with metastatic activities of NPC cells. It is not clear how mitochondrial dysfunction or mtROS can be linked to NLRP3 inflammasome activation in NPC. Our study can clarify the molecular mechanisms of mitochondria-mediated NLRP3 inflammasome activation in vitro (NPC cells) and in (mouse model). Therefore, the specific aims are as follows. Aim 1: To investigate the roles of mitochondria in NLRP3 inflammasome activation in NPC cells. Aim 2: To investigate if mitochondrial OxPhos is involved in metastatic activities of NPC cells Aim 3: To determine the effect of NLRP3 inflammsome activation on mitochondrial OxPhos-mediated metastatic activity in NPC cells Our study may open a new direction for future therapy or drug development for cancer through inflammation modulation.

Project ID:PC10507-0258
External Project ID:MOST105-2320-B182-034-MY3