Journal Article

Cyclooxygenase Enzymes and Prostaglandin Receptors: Insights into Mechanisms and Control of Uterine Pathology

Jabbour, Henry, Sales, Kurt J.

2008

Overview

Cyclooxygenase (COX) enzymes catalyze the rate-limiting biosynthesis of prostaglandins (PG). Following biosynthesis PG exert an autocrine/paracrine function locally by coupling to specific G-protein coupled receptors. Over the past decade, many epidemiological, pharmacological and laboratory studies using in vitro and in vivo model systems of targeted gene disruption in mice have provided conclusive evidence for a role for COX enzymes, PG and PG receptors in pathophysiology. We have established elevated expression of COX enzymes (COX-1 and COX-2), PG (PGE2 and PGF2α) and PG receptors (EP2/EP4 and FP receptor) in pathologies of the female reproductive tract. In cervical and endometrial carcinomas, the expression of COX enzymes, PG and PG receptors are up-regulated in neoplastic epithelial cells as well as endothelial cells of the microvasculature compared with normal tissue. We elucidated the role of COX-1 and COX-2 in cervical and endometrial carcinomas using an in vitro HeLa Tet-Off system to inducibly express COX-1 or Ishikawa cell line stably expressing COX-2. We found that elevated COX enzyme expression in vitro, up-regulated the biosynthesis of PG and induced the expression of PG receptors. Coincident with the up-regulation of PG and PG receptors, we also observed up-regulation of potent angiogenic factors and down-regulation of anti-angiogenic factors. These findings lead to the suggestion that COX enzyme inhibitors may be of potential benefit as therapeutic regimens for cervical and endometrial carcinomas as has been recommended for other types of carcinomas highly expressing COX enzymes. Subsequently we have elucidated the signal transduction pathways mediating the role of PG via their specific receptors in cervical and endometrial carcinomas. For example, activation of the FP receptor in endometrial cancer cells can promote rapid cytoskeletal reorganization, formation of focal adhesion complexes and integrin-extracellular matrix engagement to promote cancer cell adhesion and migration to facilitate metastasis. Moreover, we have discovered that coincident with these dynamic changes in cell morphology, adhesion and migration, FP receptor signaling also promotes the production of potent angiogenic factors such as VEGF and FGF2. Following release, these angiogenic factors act in a paracrine manner to promote vascular branching and sprouting and endothelial cell proliferation. Taken together, our research has elucidated the role of COX enzymes and PG receptor signaling in cervical and endometrial carcinomas as potent regulators of cell movement and vascular function. These findings have highlighted the use of specific PG receptor antagonists or inhibitors of key signal transduction pathways to inhibit the adverse effects of elevated PG signaling in uterine carcinomas.

• Publisher: Oxford University Press
• Subject: Angiogenesis / Autocrine signalling / Biosynthesis / Cancer / Cell adhesion / Cell migration / Cell proliferation / Cervical carcinoma / Cervix / Cyclooxygenase-1 / Cyclooxygenase-2 / Cytoskeleton / Down-regulation / Endometrium / Endothelial cells / Enzyme inhibitors / Enzymes / Epithelial cells / Extracellular matrix / Metastases / Microvasculature / Paracrine signalling / Reproductive system / Signal transduction / Uterus / Vascular endothelial growth factor