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

• Published in: Journal of cancer research and clinical oncology 2020-09, Vol.146 (9), p.2219-2229
• Main Authors: Yaw, Alan Cheuk Keong, Chan, Elaine Wan Ling, Yap, Jeremy Kean Yi, Mai, Chun Wai
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - chemically induced; Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Apoptosis; Cancer Research; Caspase-1; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Survival - drug effects; Cell viability; Cytokines - metabolism; Furans; Hematology; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; IL-1β; Indenes; Inflammasomes; Inflammasomes - drug effects; Inflammasomes - metabolism; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Inflammation Mediators - metabolism; Interleukin-1beta - metabolism; Internal Medicine; Kinases; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Medicine; Medicine & Public Health; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Oncology; Original Article – Cancer Research; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - chemically induced; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Sulfonamides; Sulfones - pharmacology; Tumor cell lines; Western blotting
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-020-03274-y

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.