The effects of NLRP3 inflammasome inhibition by MCC950 on LPS-induced pancreatic adenocarcinoma inflammation

Abstract

Purpose: Pancreatic cancer is a lethal form of cancer that can be triggered by prolonged or acute inflammation of the pancreas. Inflammation have been shown to be regulated by a group of key protein molecules known as the inflammasomes. The NLRP3 inflammasome is the most studied inflammasome and have been strongly implicated to regulate cancer cell proliferation. Therefore, this study aimed to examine the regulation of NLRP3 inflammasome under LPS-induced inflammation and its role in modulating cell proliferation in a panel of pancreatic cancer cells.

Methods: The effects of LPS-induced NLRP3 activation in the presence or absence of MCC950, NLRP3-specific inhibitor, was tested on a panel of three pancreatic cancer cell lines (SW1990, PANC1 and Panc10.05). Western blotting, cell viability kits and ELISA kits were used to examine the effects of LPS-induced NLRP3 activation and inhibition by MCC950 on NLRP3 expression, cell viability, caspase-1 activity and cytokine IL-1β, respectively.

Results: LPS-induced inflammation in the presence of ATP activates NLRP3 that subsequently increases pancreatic cancer cell proliferation by increasing caspase-1 activity leading to overall production of IL-1β. The inhibition of the NLRP3 inflammasome activation via the specific NLRP3 antagonist MCC950 was able to reduce the cell viability of pancreatic cancer cells. However, the efficacy of MCC950 varies between cell types which is most probably due to the difference in ASC expressions which have a different role in inflammasome activation.

Conclusion: There is a dynamic interaction between inflammasome that regulates inflammasome-mediated inflammation in pancreatic adenocarcinoma cells.

Keywords: Apoptosis-associated speck-like protein (ASC); LPS-induced inflammation; MCC950; NLPR3 inflammasome inhibitor; NLRP3 inflammasome; Pancreatic cancer.

Fig. 1

Cell viability of pancreatic cancer cells under LPS and/or ATP stimulation in the presence or absence of MCC950

Fig. 2

a Protein expression of apoptosis-associated speck-like protein (ASC) in SW1990, PANC1 and Panc10.05 pancreatic cancer cell lines. b Protein expression of NLRP3 in Panc10.05, SW1990 and PANC1 pancreatic cancer cell lines. c GEO analysis of inflammasomes of normal versus tumour pancreatic tissue

Fig. 2

a Protein expression of apoptosis-associated speck-like protein (ASC) in SW1990, PANC1 and Panc10.05 pancreatic cancer cell lines. b Protein expression of NLRP3 in Panc10.05, SW1990 and PANC1 pancreatic cancer cell lines. c GEO analysis of inflammasomes of normal versus tumour pancreatic tissue

Fig. 3

a Expression of caspase-1 in SW1990, PANC1 and Panc10.05 pancreatic cancer cell lines. b Expression of IL-1β in Panc10.05, SW1990 and PANC1 pancreatic cancer cell lines