Page 69 - Vitamin D and Cancer

56 A.V. Krishnan and D. Feldman

3.3.1.1 COX-2

Cyclooxygenase (COX)/prostaglandin endoperoxidase synthase is the rate-limiting
enzyme that catalyzes the conversion of arachidonic acid to PGs and related
eicosanoids. COX exists as two isoforms, COX-1, which is constitutively expressed
in many tissues and cell types and COX-2, which is inducible by a variety of
stimuli. COX-2 is regarded as an immediate-early response gene whose expression
is rapidly induced by mitogens, cytokines, tumor promoters, and growth factors
[37]. Genetic and clinical studies indicate that increased COX-2 expression is one
of the key steps in carcinogenesis [45]. Long-term use of NSAIDs or aspirin has
been shown to be associated with a decrease in death rate from several cancers
such as colorectal, stomach, breast, lung, prostate, bladder, and ovarian cancers
[15, 16, 46, 47].
Several studies suggest a causative and/or stimulatory role for COX-2 in prostate
tumorigenesis and demonstrate its overexpression in prostate adenocarcinoma [48, 49].
However, not all PCa are associated with elevated COX-2 expression [50, 51]. Zha
et al. [51] did not find consistent overexpression of COX-2 in established PCa.
However, they detected appreciable COX-2 expression in areas of proliferative
inflammatory atrophy (PIA), lesions that have been implicated in prostate carcino-
genesis. Silencing of COX-2 in metastatic PCa cells induces cell growth arrest and
causes morphological changes associated with enhanced differentiation, highlight-
ing the role of COX-2 in prostate carcinogenesis [52]. COX-2 protein expression in
prostate biopsy cores and PCa surgical specimens is inversely correlated with dis-
ease-free survival [53]. A recent analysis of archival radical prostatectomy
specimens concluded that COX-2 expression was an independent predictor of
recurrence [54]. Elevated COX-2 protein levels have been reported in ~40% of
invasive breast carcinomas [4]. NSAIDs inhibit the development of BCa in a variety
of animal models (reviewed in [4]). Interestingly, PG signaling stimulates the tran-
scription of the aromatase gene [55] and a positive correlation between COX-2 and
aromatase expression in human breast carcinomas reflects this causal link [56, 57].
COX-2 overexpression in BCa correlates with features of aggressive breast disease
including larger tumor size, high-grade, increased proliferation, negative hormone
receptor status, and overexpression of the Her-2/neu oncogene [58–61]. An inverse
relationship between COX-2 protein levels and disease-free survival in BCa
patients has also been shown [59, 62]. Epidemiological observations show a signifi-
cant reduction in the incidence of CRC among chronic users of NSAIDs (reviewed
in [63]). A critical link between COX-2 and colorectal tumorigenesis was demon-
strated when Apc delta716 mutant mice were mated to COX-2 knockout mice and
a dramatic reduction in the number of intestinal polyps was seen in the doubly null
progeny compared to COX-2 wild-type mice [64]. COX-2 protein is significantly
overexpressed in CRC [38, 39, 63] and increased COX-2 expression correlates with
a larger polyp size and progression to invasive carcinoma [65, 66].
Local production of PGs at the tumor sites by infiltrating inflammatory cells also
increases the risk of carcinogenesis and/or cancer progression [3, 39, 51, 67, 68].
In colon cancer, COX-2 expression has been found in the carcinoma cells as well