Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: an update on the molecular mechanisms.

Abstract

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risks for esophageal, gastric and colon cancers as well as other solid tumors. The antitumor effect of NSAIDs is mediated through cyclooxygenase-2 (COX-2)-dependent and -independent regulation of oncogenic and tumor-suppressive pathways. Recent discoveries have shed new light on the regulation of COX-2 at the molecular level in these cancers. Moreover, prostaglandin E(2) (PGE(2)), a COX-2-derived eicosanoid, has been found to affect numerous tumorigenic processes. In this connection, PGE(2) activates multiple intracellular signaling pathways, including (1) transactivation of epidermal growth factor receptor (EGFR); (2) protein kinase C-dependent, EGFR-independent activation of extracellular signal-regulated kinase (ERK) and the transcription factors activator protein-1 and c-Myc; (3) G-protein-mediated activation of beta-catenin/TCF-dependent transcription. Activation of these signaling pathways by PGE(2) is mediated by EP receptors whose inhibitors suppress gastrointestinal carcinogenesis. Taken together, COX-2 expression is dysregulated in many types of cancer and COX-2-derived PGE(2) elicits multiple oncogenic signals to promote carcinogenesis. Targeting PGE(2) signaling by EP receptor antagonists holds promise for the development of targeted therapy for the treatment of cancer.

• Authors: William Ka Kei Wu, Joseph Jao Yiu Sung, Chung Wa Lee, Jun Yu, Chi Hin Cho
• Journal: Cancer letters (Cancer Lett) Vol. 295 Issue 1 Pg. 7-16 (Sep 01 2010) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 20381235 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents
• Receptors, Prostaglandin E
• Cyclooxygenase 2
• Dinoprostone

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cyclooxygenase 2 (genetics, metabolism)
• Dinoprostone (metabolism)
• Gastrointestinal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• Receptors, Prostaglandin E (antagonists & inhibitors, metabolism)
• Signal Transduction
• Up-Regulation