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Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
Published on: July 28, 2010
Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: an update on the molecular mechanisms
William Ka Kei Wu1, Joseph Jao Yiu Sung, Chung Wa Lee
1Institute 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
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.
Insights
Nonsteroidal anti-inflammatory drugs (NSAIDs) show potential in reducing cancer risk by targeting cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) pathways. Inhibiting these pathways may offer new cancer treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) are linked to reduced risks of esophageal, gastric, colon, and other solid tumors.
- The anti-cancer effects of NSAIDs involve cyclooxygenase-2 (COX-2)-dependent and -independent regulation of cancer-related pathways.
- Cyclooxygenase-2 (COX-2) regulation and its role in cancer have been elucidated at the molecular level.
Purpose of the Study:
- To explore the molecular mechanisms underlying the antitumor effects of NSAIDs.
- To investigate the role of prostaglandin E(2) (PGE(2)) in cancer development and progression.
- To evaluate the therapeutic potential of targeting PGE(2) signaling pathways in cancer treatment.
Main Methods:
- Review of recent discoveries on COX-2 regulation in cancer.
- Analysis of how PGE(2) activates intracellular signaling pathways, including EGFR, ERK, activator protein-1, c-Myc, and beta-catenin/TCF.
- Examination of the role of EP receptors in mediating PGE(2) effects and their inhibition in suppressing gastrointestinal carcinogenesis.
Main Results:
- NSAID use is associated with decreased risks for various solid tumors.
- PGE(2), a COX-2 metabolite, promotes tumorigenesis by activating multiple oncogenic signaling pathways.
- EP receptor antagonists have demonstrated suppression of gastrointestinal carcinogenesis.
Conclusions:
- Dysregulated COX-2 expression and PGE(2)-mediated signaling are implicated in many cancers.
- Targeting PGE(2) signaling via EP receptor antagonists represents a promising strategy for novel cancer therapies.
- Further research into NSAIDs and their molecular targets could lead to advanced cancer treatment modalities.
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