Cyclooxygenase-2 in Prostate Cancer
By Sanjeev Madaan, MBBS, MS, FRCS, El-Nasir Lalani, BSc(hons), MBChB, MRCPath, PhD, and Paul D. Abel, ChM, FRCS(Eng), FRCS(Ed)
Prostate cancer (pc) is the most commonly diagnosed adenocarcinoma and the second leading cause of cancer death after lung cancer in men in the Western world. In 1998 alone, it was estimated that about 185,000 new cases (30% of all new cancers in men) were diagnosed and more than 39,000 patients died from PC in the United States.1 Approximately 50% of patients present with or develop incurable, metastatic disease.2 Although most patients with advanced PC initially respond to androgen ablation treatment, relapse to an androgen-independent state occurs after a period of approximately two years, followed by death about six months later.3 Therefore, much research is being directed toward understanding the mechanisms involved in development and progression of PC and developing new strategies for prevention and cure. The present article reviews the role of cyclooxygenase-2 (COX-2) in the development and progression of PC.
Cyclooxygenases and Prostaglandins
The prostaglandins (PGs) are a diverse group of autocrine and paracrine hormones that mediate many cellular and physiological processes. They were named PGs because they were first discovered in seminal fluid in high concentrations, hence "prostate gland hormone." PGs are synthesized from arachidonic acid, which normally is esterified in membrane phospholipids and is released through the activation of cellular phospholipases (see Figure). The enzyme responsible for the first rate-limiting step in the production of PG from arachidonic acid is cyclooxygenase (COX), also previously known as PG H synthase, PG G/H synthase, and PG endoperoxide synthase.4 It exists as two isoforms, COX-1 and COX-2, which are encoded by separate genes located on separate chromosomes (COX-1 on chromosome 9 and COX-2 on chromosome 1). They are highly related at the DNA, RNA, and protein level. COX-1 and COX-2 consist of 576 and 587 amino acids, respectively, and they share approximately 60% primary sequence homology. COX-1 and COX-2 exist as integral membrane glycoprotein homodimers and are found on the luminal surfaces of the endoplasmic reticulum and nuclear envelope.5 Traditional nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, act by inhibiting COX activity (see Figure).
Although COX-1 and COX-2 genes are similar, they are under profoundly different mechanisms of control and fulfill different physiological functions. COX-1 is expressed constitutively and is involved in housekeeping processes that require immediate generation of prosta-noids (e.g., vascular homeostasis, water reabsorption, and gastric acid secretion). COX-2, on the other hand, is an inducible isoform up-regulated by specific stimuli (e.g., mitogens, growth factors, glucocorticoids, and cytokines) in different cell types and controlled at both the transcriptional and post-translational levels.6 COX-2 is involved in differentiative processes, such as inflammation, ovulation, and labor, in which only transient PG production is required.6
COX-2 also has been shown to be up-regulated in many cancers, and several experimental studies indicate that COX-2 may be involved in the pathogenesis of cancer. Recent work on rat mammary glands suggests that hormonal influences on cancer development also may be mediated by COX-2 gene expression and PG synthesis.7,8 COX-2 inhibitors have been shown to be chemopreventive against colon and lung cancers in mouse models.9,10 Furthermore, COX-2/ApcD716 double gene knockout mice show a decrease in the number and size of intestinal polyps when compared with ApcD716 knockout mice.11
Diet and Prostaglandins in Prostate Cancer
Epidemiological studies of PC have revealed an association between an increased PC incidence and high dietary fat intake.12 In both PC cells and animal models of PC, n-6 polyunsaturated fatty acids (PUFAs) present in vegetable oils have been shown to be proliferative, whereas n-3 PUFAs in fish oils have been shown to be inhibitory.12 NSAIDs inhibit the promoting effects of n-6 PUFA-rich diets, suggesting a role for PG synthesis.12
Compared to their benign counterparts, enhanced PG production has been noted in experimentally induced and naturally occurring tumors. Shaw et al measured PGE2 and PGF2a levels in plasma and tumor effusions of three tumor sublines of the Dunning R-3327 rat prostate adenocarcinoma.13 Effusions of the highly metastatic Mat LyLu subline possessed significantly higher levels of PGE2 compared to that of the non-metastasizing H and G sublines. Rose and Connolly reported growth inhibition of androgen-responsive and androgen-unresponsive human prostate cancer cells by indomethacin.14 Noble PC-bearing rats treated with PG modulators, i.e., indomethacin (a COX inhibitor), UK 38485 (a thromboxane synthetase inhibitor), and nafazatron (an anti-thrombotic agent which increases prostacyclin), had significantly lower pulmonary metastasis than untreated controls.15 Further, PGE2 has been shown to modify the tumor immune response in PC.16
The epidemiological evidence for a protective effect of NSAIDs in PC development is equivocal. In a recent population-based, case-controlled study from New Zealand, Norrish et al reported a trend toward reduced risk of advanced PC associated with regular use of NSAIDs.17 Although these associations failed to reach statistical significance, the authors suggest that COX activity has a role in PC development.
COX-2 in Prostate Cancer
O’Neill and Ford-Hutchinson analyzed COX-1 and COX-2 mRNA expression in various human tissues and found the highest levels were detected in the prostate where COX-1 and COX-2 transcripts were present in approximately equal levels.18 Evidence that increased COX-2 levels may be important in PC development comes from preliminary results in human and canine prostates.19-21 We have studied COX-1 and COX-2 expression in 112 prostate cases (30 BPH and 82 PC) using immunohistochemistry and immunoblotting. We found significant COX-2 overexpression in tumor cells compared to benign glands; however, COX-1 expression in tumor cells was similar to benign glands.22 There also was a significant positive correlation between COX-2 expression and increasing tumor grade. Our findings are consistent with human PC data showing radiolabelled arachidonic acid is converted to PGE2 at a rate almost 10-fold faster than that observed in benign prostates.23 Our data suggest that COX-2, rather than COX-1, is likely to be responsible for this increased conversion rate.
There are multiple mechanisms through which COX-2 may play a role in carcinogenesis and some or all of these may be involved in PC development and progression. Many are likely to result from COX-2-induced increases in PG synthesis. Evidence that increased PG synthesis has both growth-promoting and positive feedback effects in PC comes from a study by Tjandrawinata et al.24 They showed that PC cell treatment with exogenous PGE2 resulted in increased mitogenesis (that was inhibited by the NSAID flubiprofen) and COX-2 up-regulation. COX-2 overexpression has been shown to up-regulate Bcl-2 expression with an associated decrease in apoptosis.25 Accordingly, the human PC cell line LNCaP, which overexpresses COX-2, exhibits apoptosis induction and Bcl-2 expression down-regulation when treated with NS-398, a selective inhibitor of COX-2 enzyme function.26 Bcl-2 expression has been associated closely with the androgen-independent PC phenotype and represents a potential pathway through which COX-2 may induce PC progression to an androgen-independent state.3
Other effects of COX-2 overexpression that may contribute to the malignant phenotype include decreased E-Cadherin expression with consequent loss of cell-to-cell adhesion, matrix-metalloproteinase overexpression with an associated increase in invasiveness, and modulated production of angiogenic factors by cancer cells.25-28 COX-2 overexpression in cancer cells also has been shown to inhibit immune surveillance and increase metastatic potential.27,29 Furthermore, as shown in bladder cancer, COXs may play a role in the bioactivation of several polycyclic aromatic hydrocarbons and aromatic amines, two classes of carcinogens that induce extrahepatic neoplasia.30
There is evidence that COX-2 may play a role in PC development and progression, although more work needs to be done to understand the mechanisms of action involved. Recently, COX-2-specific inhibitors have become available. They have lower side effect profiles compared to traditional NSAIDs and have been shown to have antitumor properties. In a rat model, COX-2 inhibitors increased tumor response to radiation treatment without increasing the radiation effects on normal tissues.31 The role of COX-2 inhibitors in PC prevention and treatment (either alone or as an adjunct to chemotherapy or radiotherapy) is worthy of further exploration. (Dr. Madaan is a Clinical Research Fellow; Dr. Lalani is a Professor in Molecular and Cellular Pathology; and Dr. Abel is a Reader and Honorary Consultant Urologist, Head of Section of Academic Urology, at the Imperial College School of Medicine, London, England.)
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