Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: an update on the molecular mechanisms.
W. Wu, J. Sung, C. W. Lee
Sep 1, 2010
Citations
156
Citations
Quality indicators
Journal
Cancer letters
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Semantic Scholar
Key Takeaway Key Takeaway: COX-2 dysregulation in various cancers promotes carcinogenesis, and targeting PGE(2) signaling with EP receptor antagonists holds promise for developing targeted cancer treatments.
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.