Abstract
Bacterial products (e.g., LPS) are viewed as critical stimuli in inflammation-associated cancer. Cyclooxygenase 2 (COX-2), a major effector of LPS, and EGFR, are key to carcinogenesis, notably in the hepatobiliary tract. In this study, we tested the hypothesis that LPS can initiate an interaction between the epidermal growth factor receptor (EGFR) and COX-2 pathways. We examined the effect of LPS in biliary carcinoma cells that displayed constitutive COX-2 expression and PGE(2) production and in normal human biliary epithelial cells in which COX-2/PGE(2) expression was virtually absent. LPS induced early phosphorylation of EGFR and ERK1/2 in both types of cells, which reached maximum levels within 30 min (first phase). However, only the carcinoma cells showed a second significant rise in both EGFR and ERK phosphorylation 6 h after exposure to LPS (second phase). Inhibition of COX-2/PGE(2) production prevented the second, but not the first, phase of EGFR and ERK1/2 phosphorylation, implicating COX-2/PGE(2) in the second phase of phosphorylation. LPS induced COX-2-derived PGE2 production at 4 h, which was before the rise in the second phosphorylation that occurred at 6 h. Exogenous PGE(2) also caused EGFR activation via a signaling pathway involving TACE-dependent TGF-alpha release. Inhibition of the second phase of EGFR phosphorylation with EGFR or COX-2 inhibitor prevented LPS-induced cell invasion in vitro, demonstrating the biological importance of this COX-2 feedback signaling in cancer cells. We conclude that LPS triggers a positive feedback loop involving COX-2/PGE(2) in biliary carcinoma cells and that this second phase of EGFR phosphorylation is implicated in cell invasion by LPS.
Highlights
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Because normal human biliary epithelial (NHBE) and Mz-ChA-1 cells display different expression patterns of Cyclooxygenase 2 (COX-2)/PGE2, we examined the effect of LPS on the temporal activation of an epidermal growth factor receptor (EGFR) cascade: incubation of NHBE cells with LPS increased EGFR phosphorylation, which occurred as early as 15 min, was maximal at ϳ30 min, and decreased by 2 h (Fig. 2A)
We show that in biliary carcinoma cells, LPS, a pathophysiological stimulus, induces biphasic EGFR phosphorylation: the early phase occurs at ϳ30 min after stimulation, involving TACE-dependent EGFR ligand release; the delayed phase occurs at ϳ6 h after stimulation via a signaling pathway involving COX-2/PGE2-dependent TACE activation and EGFR ligand release
Summary
COX-2, cyclooxygenase 2; EGFR, epidermal growth factor receptor; GPCR, G-protein coupled receptor; siRNA, small interfering RNA; TACE, TNF-␣-converting enzyme; TAPI-1, TNF-␣ protease inhibitor 1; EGF, epidermal growth factor; SFM, serum-free medium; NHBE, normal human biliary epithelial. LPS induces COX-2 and PGE2 production in a variety of epithelia, notably in the digestive and hepatobiliary tracts (9 – 12). Among different signaling pathways induced by LPS, activation of an EGFR cascade has been identified previously in the respiratory epithelium [15] and recently in biliary epithelial cells [12]. LPS has the ability to stimulate both the EGFR and COX-2/PGE2 pathways in epithelial cells. In inflammatory biliary tract diseases and associated carcinomas, the epithelium is exposed to high concentrations of LPS [14, 16, 17]. The novel feedback loop and the finding that this loop is important in cell invasion in response to an inflammatory stimulus (LPS) suggest that this feedback signaling pathway may play an important role in the pathophysiology of biliary carcinomas and inflammatory biliary diseases
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