| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
,
* Université Pierre et Marie Curie, University of Paris 06, UMRS-893, Centre de Recherche Saint-Antoine, Paris;
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé-893, Centre de Recherche Saint- Antoine, Paris;
Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Service de Chirurgie Digestive, Paris;
Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Service de Biochimie-Hormonologie, Paris, France; and
¶ Cardiovascular Research Institute and Department of Medicine and Department of Physiology, University of California, San Francisco, CA 94143
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 PGE2 production and in normal human biliary epithelial cells in which COX-2/PGE2 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/PGE2 production prevented the second, but not the first, phase of EGFR and ERK1/2 phosphorylation, implicating COX-2/PGE2 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 PGE2 also caused EGFR activation via a signaling pathway involving TACE-dependent TGF-
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/PGE2 in biliary carcinoma cells and that this second phase of EGFR phosphorylation is implicated in cell invasion by LPS.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Grant support was provided by the Association pour la Recherche sur le Cancer (Grant 3307) and by the Institut National du Cancer (Grant PL-027).
2 L.F. and M.X.G.S. contributed equally.
3 Address correspondence and reprint requests to Dr. Jay A. Nadel, Cardiovascular Research Institute and Department of Medicine and Department of Physiology, University of California, San Francisco, 513 Parnassus Avenue, Room S1183, San Francisco, CA 94143. E-mail address: jay.nadel{at}ucsf.edu
4 Abbreviations used in this paper: 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.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
