Many actions of cyclooxygenase‐2 in cellular dynamics and in cancer

Abstract

Cyclooxygenase-2 (COX-2) is the inducible isoform of cyclooxygenase, the enzyme that catalyzes the rate-limiting step in prostaglandin synthesis from arachidonic acid. Various prostaglandins are produced in a cell type-speci®c manner, and they elicit cellular functions via signaling through G-protein coupled membrane receptors, and in some cases, through the nuclear receptor PPAR. COX-2 utilization of arachidonic acid also perturbs the level of intracellular free arachidonic acid and subsequently affects cellular functions. In a number of cell and animal models, induction of COX-2 has been shown to promote cell growth, inhibit apoptosis and enhance cell motility and adhesion. The mechanisms behind these multiple actions of COX-2 are largely unknown. Compelling evidence from genetic and clinical studies indicates that COX-2 upregulation is a key step in carcinogenesis. Overexpression of COX-2 is suf®cient to cause tumorigenesis in animal models and inhibition of the COX-2 pathway results in reduction in tumor incidence and progression. Therefore, the potential for application of nonsteroidal anti-in¯ammatory drugs as well as the recently developed COX-2 speci®c inhibitors in cancer clinical practice has drawn tremendous attention in the past few years. Inhibition of COX-2 promises to be an effective approach in the prevention and treatment of cancer, especially colorectal cancer.

Cyclooxygenase‐2 expression in human pituitary tumors

“…The exact mechanism by which COX-2 overexpression promotes tumor cell proliferation is unclear. 21 One possibility is that overexpression of COX-2 increases tumoral levels of prostaglandins, thereby promoting tumor progression by acting on differentiation and growth factors. Consistent with this hypothesis, it has been reported that prostaglandins increase tumor cell proliferation and prevent apoptosis by stimulating the expression of Bcl2, an antiapoptotic protein.…”

“…Overexpression of COX-2 also increases production of proangiogenic factors and decreases E-cadherin, a cell adhesion molecule indispensable for tumor growth, invasion, and metastasis. [17][18][19][20][21] We evaluated whether COX-2 expression occurs in adenohypophysial tumors and assessed its utility as a marker of tumor behavior. Pituitary tumors are heterogeneous, exhibiting a multifactorial etiology and pathogenesis.…”

Allellic variants in regulatory regions of cyclooxygenase-2: association with advanced colorectal adenoma

“…Cyclooxygenase 2 generates multifunctional lipid metabolites, prostaglandins, which are implicated in various cellular processes including proliferation, inflammation, invasion, angiogenesis, and apoptosis (Cao and Prescott, 2002). It is estimated that more than 85% of human colon cancers and 50% of colorectal adenomas have elevated levels of Cox-2 (Eberhart et al, 1994).…”

Increased NF-κB DNA binding but not transcriptional activity during apoptosis induced by the COX-2-selective inhibitor NS-398 in colorectal carcinoma cells

“…This stems from the ability of NSAIDs to inhibit invasion and angiogenesis and induce apoptosis, indicating the importance of COX-2 in metastasis (reviewed in Cao and Prescott, 2002). Their use in a therapeutic setting would justify the use of relatively high doses of NSAIDs, which are believed to have both COX-dependent and COX-independent effects (reviewed in Turini and DuBois, 2002).…”