Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: an update on the molecular mechanisms.
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.
Wu
William Ka Kei
WK
Institute of Digestive Diseases, LKS Institute of Heath Sciences and Department of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. wukakei@cuhk.edu.hk
Sung
Joseph Jao Yiu
JJ
Lee
Chung Wa
CW
Yu
Jun
J
Cho
Chi Hin
CH
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D018078:Receptors, Prostaglandin E; D051546:Cyclooxygenase 2; D015232:Dinoprostone