Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect.

Abstract

Evidence from epidemiological studies, clinical trials, and animal experiments indicates that inhibitors of prostaglandin synthesis lower the risk of colon cancer. We tested the hypothesis that abnormal expression of prostaglandin H synthase 2 (PHS-2), which can be induced by oncogenes and tumor promoters, occurs during colon carcinogenesis by examining its level in colon tumors. Human colon cancers were found to have an increased expression of PHS-2 mRNA compared with normal colon specimens from the same patient (n = 5). In situ hybridization showed that the neoplastic colonocytes had increased expression of PHS-2 (n = 4). Additionally, five colon cancer cell lines were shown to express high levels of PHS-2 mRNA even in the absence of a known inducer of PHS-2. To study the basis for this increased gene expression, we transfected a colon cancer cell line, HCT-116, with a reporter gene containing 2.0 kb of the 5' regulatory sequence of the PHS-2 gene. Constitutive transcription of the reporter ge'w was observed, whereas normal control cell lines transcribed the reporter only in response to an exogenous agonist. We conclude that PHS-2 is transcribed abnormally in human colon cancers and that this may be one mechanism by which prostaglandins or related compounds that support carcinogenesis are generated.The study of the genetic events leading to colon carcinoma has shown that early mutations generate premalignant changes in the colonic epithelium. It is also likely that additional mutations and epigenetic progression factors are required for the development of a malignancy (1). Many studies [reviewed by Marnett (2)] have suggested that prostaglandins may be one of these progression factors. For example, colon cancers secrete more prostaglandins than normal colon tissue (2, 3). Additionally, reactive byproducts of prostaglandin synthesis might be relevant mutagens (2). The regular use of medications that inhibit prostaglandin synthesis (e.g., aspirin and indomethacin) is associated with a decreased risk of death from colon cancer (4), decreased incidence of colon cancer (5-8), and decreased incidence of colon adenomas (6, 7, 9, 10). Inhibitors of prostaglandin synthesis protect against chemically induced colon cancer in animal models (2). These inhibitors appear to act early in the process of colon carcinogenesis, as the use of an inhibitor in patients with adenomatous polyposis coli reduced the number and size of polyps by '60% (11,12).The key step in the conversion of arachidonic acid to prostaglandins is catalyzed by prostaglandin H synthase (PHS, also known as cyclooxygenase), and inhibition of this reaction by aspirin, indomethacin, and other anti-inflammatory drugs accounts for all or most of their therapeutic effects. PHS converts free arachidonic acid into prostaglandin H2, which is a pivotal metabolite that serves as the precursor for terminal prostaglandins. Specific synthases catalyze the conversion of prostaglandin H2, and the products of a given tissue depend on which of these enzymes is express...

Regulation of Cyclooxygenase-2 pathway by HER2 receptor

“…To further con®rm the role of NDF in the transcriptional regulation of COX-2 gene, we transiently transfected chimeric luciferase gene fused with 5' region of COX-2 promoter (Kutchera et al, 1996) and Figure 5 Constitutive activation of the HER2/HER3 pathway upregulates the expression of COX-2. (A) Subcon¯uent LS174T cells, cultured in the presence of 10% serum (lanes 1 and 2) or 0% serum (lanes 3 and 4), were treated with control IgG (lane 1), anti-HER3 mAb (lane 2) or NDF (lane 4).…”

“…Inhibition of HER2/HER3 signaling by an anti-HER3 mAb against the ligand binding site resulted in a decrease in the levels of constitutively activated HER2/Introduction Accumulating evidence suggests that colorectal tumorigenesis may be regulated by the growth factorinducible form of cyclooxygenase-2 (COX-2), an enzyme responsible for the conversion of arachidonic acid to prostaglandins Smith et al, 1996). PGEs appear to play a variety of roles in the gastrointestinal tract, including participation in physiological secretion and motility, and also in pathologic processes such as neoplasia (Kutchera et al, 1996;Eberhart, 1994;DuBois et al, 1996). The primary PGEs generated in the colorectum appear to be PGE2 (Smith et al, 1996).…”

“…The primary PGEs generated in the colorectum appear to be PGE2 (Smith et al, 1996). Recent studies have shown the increased levels of COX-2 and PGE2 in colorectal adenocarcinomas compared to adjacent normal-appearing mucosa (Kutchera et al, 1996;Eberhart, 1994;DuBois, et al, 1996) and inhibition of COX-2 enzyme by speci®c COX-2 inhibitors reduces tumor formation, and regresses pre-existing tumors (Boolbol et al, 1996;Sheng et al, 1997;Chiu et al, 1997). The potential neoplastic role of COX-2 expression was demonstrated by Tsujii and DuBois (1995).…”

JTE‐522, a selective cyclooxygenase‐2 inhibitor, inhibits induction but not growth and invasion of 1,2‐dimethylhydrazine‐induced tubular adenocarcinomas of colon in rats

“…It is now known that nonselective NSAIDs inhibit activities of cyclooxygenases (COX), and inhibition of COX-2 may well explain their chemopreventive effect, whereas inhibition of COX-1 is believed to be responsible for many of their adverse side effects. 3,4 COX-2 has been demonstrated to be overexpressed in human colorectal cancers 5,6 and in chemically induced colon cancers in rodents, 7 and has been suggested to be an important target for both cancer prevention and/or therapy. Furthermore, recently developed selective COX-2 inhibitors such as celecoxib have been shown to suppress colon carcinogenesis in experimental animals 8 -10 and humans with less toxicity than nonselective NSAIDs.…”

Activation of thromboxane receptor α induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells

“…Increase in tissue level of TXB 2 is known to be the result of an enhancement of TXAS activity leading to increased synthesis of TXA 2 which may induce the expression of COX-2. The expression of COX-2 and the elevation of its metabolite levels have been broadly studied in both experimental animals and human tumors [34,35]. COX-2 up-regulation has been observed in lung cancer as well as in cancers of colon, stomach, liver, pancreas, breast, and skin and thought to play a critical role in cancer progression.…”