Famotidine promotes inflammation by triggering cell pyroptosis in gastric cancer cells

Jin Huang,Yabei Liu,Chengtao Weng,Gaofei Fan,Pingsheng Fan,Xiaohong Duan,Lili Tang,Guohong Yang,Tengyue Zhang,Yang Wu,Miao Liu

doi:10.1186/s40360-021-00533-7

Jin Huang, Yabei Liu + Show 9 more

Open Access

https://doi.org/10.1186/s40360-021-00533-7

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Abstract

BackgroundCell pyroptosis has been characterized by cell swelling and pro-inflammatory factors release to aggravate inflammatory reaction., such as interlukin-1 beta (IL-1β) and interlukin18 (IL-18). However, the function of famotidine, an antagonist of histamine H2-receptor antagonists, in cell pyroptosis remained unknown.MethodsReal-time quantitative PCR (qPCR), western blotting (WB), LDH release assay and enzyme linked immunosorbent assay (Elisa) combined with inhibitor were performed to analyze the effect of famotidine on cell pyroptosis-related gene expression.ResultsIn this study, we found that famotidine (300 μm) treatment led to a phenomenon of cell pyroptosis as confirmed by LDH assay. Further results showed that famotidine triggered cell pyroptosis in gastric cancer cells by activation of NLPR3 inflammasomes including ASC, Caspase-1 and NLRP, leading to enhanced IL-18, not IL-1β, mature and secretion. What’s more, the results also showed GSDME, not GSDMD, was increased in response to famotidine stimulation in BGC823 and AGS cells. Mechanically, phosphorylation of ERK1/2 was drastically enhanced in present with famotidine treatment, while inhibition of ERK1/2 activity by U0126 could reverse the promotion of famotidine in IL-18 secretion.ConclusionThese findings revealed a novel role of famotidine in cell pyroptosis in patients with gastric cancer, a comprehensive consideration is needed in treatment of gastric cancer.

Highlights

Cell pyroptosis has been characterized by cell swelling and pro-inflammatory factors release to aggravate inflammatory reaction., such as interlukin-1 beta (IL-1β) and interlukin18 (IL-18)
Either intrinsically or extrinsical stimulation led to apoptosis, which was attributed to the executioner caspases 3 and 7 (CASP3, CASP7) activation, resulting in proteolysis, nuclear fragmentation, and apoptotic cell death[24], while necroptotic cell death was initiated by death receptors (DRs), pattern recognition receptors (PRRs), and the necrosome formation was consisted of receptor-interacting protein kinase-1 (RIPK1) and RIPK3, which was kept in check by CASP8mediated cleavage of RIPK1 and RIPK3, such that in the presence of CASP8, the cell death mode defaults to apoptosis[25, 26]
Further analysis showed famotidine stimulation drastically increased the cell viability of BGC823 and AGS cells. in line with this, orphologically, a large number of dead cells were observed in BGC823 cells in absence with famotidine stimulation compared with that untreated control group, respectively(Fig. 1B)

Summary

Introduction

Cell pyroptosis has been characterized by cell swelling and pro-inflammatory factors release to aggravate inflammatory reaction., such as interlukin-1 beta (IL-1β) and interlukin (IL-18). Abnormal expression of NLRP3 and GSDMD is increased in gastric cancer tissue promotes GC cells proliferation and tumorigenesis via inducing Cyclin D1 (CCND1) and cell cycle-related proteins expression[13, 27], while high expression of GSDME in gastric cancer cells undergo the switch from caspase-3 dependent apoptosis to pyroptosis induced by chemotherapeutic drugs[15]. These findings demonstrated that the pyroptosis is critical in development of gastric cancer

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