Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased expression of cyclooxygenase-2 (COX-2) expression has been observed in several human tumor types and in selected animal and cell culture models of carcinogenesis, including lung cancer. Increased expression of COX-2 and production of prostaglandins appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness, and the stimulation of angiogenesis. In the present studies, we found that transforming growth factor beta1 (TGF-beta1) and epidermal growth factor (EGF) synergistically induced the expression of COX-2 and prostaglandin E2 (PGE2) production in mink lung epithelial (Mv1Lu) cells. EGF, but not PDGF or IGF-1, was able to inhibit TGF-beta1-induced apoptosis in Mv1Lu cells and this effect was blocked by NS-398, a selective inhibitor of COX-2 activity, suggesting a possible role for COX-2 in the anti-apoptotic effect of EGF receptor ligands. The combination of TGF-beta1 and EGF also significantly induced COX-2 expression in rat intestinal epithelial (RIE-1) cells and completely prevented sodium butyrate (NaBu)-induced apoptosis. The synergistic induction of COX-2 by TGF-beta1 and EGF was not observed in R1B-L17 cells, a line derived from Mv1Lu cells that lacks the TGF-beta type-I receptor. AG1478, a selective inhibitor of EGF receptor tyrosine kinase activity, completely suppressed the induction of COX-2 expression by either EGF or TGF-beta1+EGF. Also, PD98059, a specific inhibitor of MEK/ERK pathway, and SB203580, a specific inhibitor of p38 MAPK activity, significantly inhibited the induction of COX-2 in response to combined EGF and TGF-beta1. These results suggest an important collaborative interaction of TGF-beta1 and EGF signaling in the induction of COX-2 and prostaglandin production in Mv1Lu cells.
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PMID:Synergistic induction of cyclooxygenase-2 by transforming growth factor-beta1 and epidermal growth factor inhibits apoptosis in epithelial cells. 1093 98

We previously demonstrated that cyclooxygenase-2 (COX-2) was predominantly expressed in macrophages of sporadic human colonic adenomas; however, the role of COX-2-expressing cells during colon carcinogenesis has not yet been elucidated. In the present study, we showed the effect of PGE, on vascular endothelial growth factor (VEGF) production by PMA-differentiated U937 cells, a human macrophage model (H-Mac), and by human colon cancer cells T84. PGE1 dramatically induced VEGF production by H-Mac, but not that by T84. PGE1 significantly increased intracellular cAMP formation by H-Mac, but only modestly increased that by T84. 8-bromo-cAMP and cholera toxin also increased VEGF production by H-Mac. In contrast, neither of these agents modulated VEGF production by T84. EP2 and EP4 (PGE specific receptors) mRNA was expressed in both cells. PG dramatically increased VEGF production by activated macrophages, but not by cancer cells, through a specific PGE receptor-mediated process. These findings suggest that PGs produced by COX-2-expressing macrophages induce VEGF production by macrophages, but not by cancer cells, in an autocrine fashion.
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PMID:Effect of prostaglandin E1 on vascular endothelial growth factor production by human macrophages and colon cancer cells. 1096 22

Azoxymethane (AOM)-induced colonic carcinogenesis involves a number of mutations, including those in the K-ras gene and CTNNB1, that codes for beta-catenin. Prior in vitro studies have also demonstrated that wild type p21(K-ras) can be activated by epigenetic events. We identified 15 K-ras mutations in 14 of 84 AOM-induced colonic tumors by three independent methods. By single strand conformational polymorphism, we also observed mutations in 22 of 68 tumors in exon 3 of CTNNB1. A highly sensitive method was then used to measure p21ras activation levels. All tumors assayed possessing K-ras mutations had significantly higher p21ras activation levels (8.8 +/- 1.5%; n = 13) compared with that of control colon (3.7 +/- 0.4; n = 6; P < 0.05) or tumors without such mutations (4.2 +/- 0.4%; n = 70; P < 0.05). Among tumors with wild-type K-ras, there was a subset of tumors (18 of 70) that had significantly higher p21ras activation levels (8.0 +/- 0.9%; n = 18) compared with control colons. In three of four tumors examined with activated wild-type p21ras, we observed increased c-erbB-2 receptor expression and decreased Ras-GAP expression. In contrast, only one of eight tumors examined with wild-type ras and nonactivated p21ras demonstrated these alterations. Mitogen-activated protein kinase (MAPK) activation and cyclooxygenase-2 (COX-2) expression were increased in tumors with mutated or activated wild-type p21ras, compared with their nonactivated counterparts. Although beta-catenin mutations did not alter COX-2 expression or MAPK activity, mutations in either K-ras or beta-catenin significantly increased cyclin D1 expression. In contrast, in tumors with wild-type but activated p21-ras, cyclin D1 expression was not enhanced. Thus, the spectrum of changes in MAPK, COX-2, and cyclin D1 is distinct among tumors with ras or beta-catenin mutations or nonmutational activation of p21ras.
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PMID:Mutational and nonmutational activation of p21ras in rat colonic azoxymethane-induced tumors: effects on mitogen-activated protein kinase, cyclooxygenase-2, and cyclin D1. 1096 13

Expression of cyclooxygenase-2 (COX-2) in various stages of the Helicobacter pylori-associated gastric carcinogenesis pathway has not been elucidated. We investigated the distribution and intensity of COX-2 expression in premalignant and malignant gastric lesions, and monitored the changes after H. pylori eradication. Gastric biopsies from H. pylori-infected patients with chronic active gastritis, gastric atrophy, intestinal metaplasia (IM), gastric adenocarcinoma, and noninfected controls were studied. Expression of COX-2 was evaluated by immunohistochemistry and in situ hybridization. Endoscopic biopsies were repeated 1 year after successful eradication of H. pylori in a group of IM patients for comparing COX-2 expression and progression of IM. In all H. pylori-infected patients, COX-2 expression was predominantly found in the foveolar and glandular epithelium and, to a lesser extent, in the lamina propria. In the noninfected group, only 35% of cases demonstrated weak COX-2 expression. Intensity of COX-2 was not significantly different between the chronic active gastritis, gastric atrophy, IM, and gastric adenocarcinoma groups. In 17 patients with IM, COX-2 expressions in the epithelial cells and stromal cells were reduced 1 year after H. pylori eradication. However, the changes in COX-2 expression did not correlate with progression/regression of IM. Both premalignant and malignant gastric lesions demonstrate strong COX-2 expression. Successful eradication of H. pylori leads to down-regulation of COX-2 expression but failed to reverse IM at 1 year.
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PMID:Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions. 1098 Jan 12

Cyclooxygenase-2 (COX-2) is up-regulated in many cancers and is a rate-limiting step in colon carcinogenesis. Nonsteroidal antiinflammatory drugs, which inhibit COX-2, prevent colon cancer and cause apoptosis. The mechanism for this response is not clear, but it might result from an accumulation of the substrate, arachidonic acid, an absence of a prostaglandin product, or diversion of the substrate into another pathway. We found that colon adenocarcinomas overexpress another arachidonic acid-utilizing enzyme, fatty acid-CoA ligase (FACL) 4, in addition to COX-2. Exogenous arachidonic acid caused apoptosis in colon cancer and other cell lines, as did triacsin C, a FACL inhibitor. In addition, indomethacin and sulindac significantly enhanced the apoptosis-inducing effect of triacsin C. These findings suggested that unesterified arachidonic acid in cells is a signal for induction of apoptosis. To test this hypothesis, we engineered cells with inducible overexpression of COX-2 and FACL4 as "sinks" for unesterified arachidonic acid. Activation of the enzymatic sinks blocked apoptosis, and the reduction of cell death was inversely correlated with the cellular level of arachidonic acid. Inhibition of the COX-2 component by nonsteroidal antiinflammatory drugs restored the apoptotic response. Cell death caused by exposure to tumor necrosis factor alpha or to calcium ionophore also was prevented by removal of unesterified arachidonic acid. We conclude that the cellular level of unesterified arachidonic acid is a general mechanism by which apoptosis is regulated and that COX-2 and FACL4 promote carcinogenesis by lowering this level.
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PMID:Intracellular unesterified arachidonic acid signals apoptosis. 1100 42

Breast cancer is common in women all over the world, and exploration of chemopreventive approaches to this cancer is very important. Nimesulide, a selective inhibitor of cyclooxygenase-2 (COX-2), is a good candidate as a chemopreventive agent with low toxicity. We examined its effects on mammary tumor development in female Sprague-Dawley rats induced with the environmental carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Rats at 7 weeks of age received intragastric intubations of PhIP (85 mg / kg body weight) 4 times weekly for 2 weeks and were maintained on control diet (high fat diet) or experimental diet (high fat diet supplemented with 400 ppm nimesulide) throughout the experiment. COX-2 protein was over-expressed in epithelial cancer cells and stromal cells of the PhIP-induced mammary carcinomas, but was weak or not apparent in normal mammary gland cells. The development of mammary carcinomas was clearly suppressed by administration of nimesulide. The carcinoma incidence was 51% as compared to 71% for the control diet group. The average multiplicity of carcinomas in the experimental diet group was 1.2 +/- 0.2 (P < 0.05), significantly smaller than the control diet group value (2.6 +/- 0. 5). The size of carcinomas was also clearly decreased; 1.1 +/- 0.4 cm(3) / rat in experimental diet group (P < 0.05), 4.1 +/- 1.3 cm(3) / rat in the control diet group. The results therefore provide evidence that the selective COX-2 inhibitor, nimesulide, possesses chemopreventive activity against PhIP-induced mammary carcinogenesis in rats.
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PMID:Chemoprevention by nimesulide, a selective cyclooxygenase-2 inhibitor, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary gland carcinogenesis in rats. 1101 Nov 15

The intake of citrus fruits has been suggested as a way to prevent the development of some types of human cancer. Nitric oxide (NO) is closely associated with the processes of epithelial carcinogenesis. We attempted a search for NO generation inhibitors in Citrus unshiu. The active constituent was traced by an activity-guiding separation. NO and superoxide (O2-) generation was induced by a combination of lipopolysaccharide and IFN-gamma in mouse macrophage RAW 264.7 cells, and by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocyte HL-60, respectively. Expression of inducible NO synthase and cyclooxygenase 2 proteins were detected by Western blotting. The in vivo anti-inflammatory and antitumor promoting activities were evaluated by topical TPA application to ICR mouse skin with measurement of edema formation, epidermal thickness, leukocyte infiltration, hydrogen peroxide production, and the rate of proliferating cell nuclear antigen-stained cells. As a result, nobiletin, a polymethoxyflavonoid, was identified as an inhibitor of both NO and O2- generation. Nobiletin significantly inhibited two distinct stages of skin inflammation induced by double TPA application [first stage priming (leukocyte infiltration) and second stage activation (oxidative insult by leukocytes)] by decreasing the inflammatory parameters. It also suppressed the expression of cyclooxygenase-2 and inducible NO synthase proteins and prostaglandin E2 release. Nobiletin inhibited dimethylbenz[a]anthracene (0.19 micromol)/TPA (1.6 nmol)-induced skin tumor formation at doses of 160 and 320 nmol by reducing the number of tumors per mouse by 61.2% (P < 0.001) and 75.7% (P < 0.001), respectively. The present study suggests that nobiletin is a functionally novel and possible chemopreventive agent in inflammation-associated tumorigenesis.
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PMID:Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. 1101 29

The M(3) muscarinic cholinergic receptor has important physiological functions on normal colonic cells. It is frequently expressed on human colon cancer cells and is biologically active. Although it is mitogenic in certain cell models, the importance of this receptor on colon carcinogenesis is unknown. In the present study we have determined expression of the M(3) receptor on human colon cancer tissue compared with matched normal tissue and examined the downstream effect of receptor activation in the HT-29 human colon carcinoma cell line. Using reverse transcription-PCR, M(3) receptor RNA expression was detected in all matched colon carcinoma and normal specimens from eight patients. Five of the eight (62%) patients showed an up to 8-fold greater level of M(3) receptor expression in cancer compared with the matched normal tissue. Exposure of HT-29 cells to carbachol, a stable receptor agonist, results in a 10-fold increase in cyclooxygenase-2 (COX-2) protein. This induction of COX-2 protein was dose dependent and was inhibited by the cholinergic receptor antagonist N-methylscopolamine (NMS). Carbachol caused a dose-dependent increase in prostaglandin E(2) (PGE(2)), the main product of cyclooxygenase activity. The maximum stimulatory effect (40-fold increase) was noted with 1mM carbachol. The increase in PGE(2) was completely abolished by NMS and by the COX-2 selective inhibitor NS398. This suggests that the M(3) receptor mediates PGE(2) production by a mechanism involving COX-2. As COX-2 and PGE(2) are known promoters of gastrointestinal cancer, these data suggest that M(3) receptor activation may facilitate progression of colon carcinoma, in part by a COX-2-mediated cellular mechanism.
Carcinogenesis 2000 Oct
PMID:Cholinergic receptor up-regulates COX-2 expression and prostaglandin E(2) production in colon cancer cells. 1102 34

Helicobacter pylori, infecting more than 50% of the world population, results in gastritis, usually located in the antral portion of the stomach, accompanied by hypergastrinemia, the key factor in gastric and colorectal carcinogenesis. Excessive mucosal cell proliferation for many years may eventually result in gastric atrophy, cell mutation and transformation of gastric mucosal cells into gastrin-producing cells, which also express gastrin receptors serving to stimulate cell proliferation and tumor growth. These processes may be completed by the expression of cyclooxygenase-2 (COX-2) as an inflammation enzyme to release excessive amounts of PGE(2), leading to further proliferation, reduction in apoptosis, angiogenesis and tumor growth. H. pylori eradication results in complete regression of MALT lymphoma and subsequent normalisation of excessive gastrin release and COX-2 expression. Reduction of gastrin by active immunisation (gastrimmune), blocking of gastrin receptors with specific blockers and suppression of COX-2 might be helpful in inhibiting tumor growth and invasion.
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PMID:Helicobacter pylori infection and gastrin and cyclooxygenase expression in gastric and colorectal malignancies. 1103 48

There is evidence from both genetic and pharmacologic studies to suggest that the cyclooxygenase-2 (COX-2) enzyme plays a causal role in the development of colorectal cancer. However, little is known about the identity or role of the eicosanoid receptor pathways activated by COX-derived prostaglandins (PG). We previously have reported that COX-2-derived prostacyclin promotes embryo implantation in the mouse uterus via activation of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) delta. In light of the recent finding that PPARdelta is a target of beta-catenin transactivation, it is important to determine whether this signaling pathway is operative during the development of colorectal cancer. Analysis of PPARdelta mRNA in matched normal and tumor samples revealed that expression of PPARdelta, similar to COX-2, is up-regulated in colorectal carcinomas. In situ hybridization studies demonstrate that PPARdelta is expressed in normal colon and localized to the epithelial cells at the very tips of the mucosal glands. In contrast, expression of PPARdelta mRNA in colorectal tumors was more widespread with increased levels in transformed epithelial cells. Analysis of PPARdelta and COX-2 mRNA in serial sections suggested they were colocalized to the same region within a tumor. Finally, transient transfection assays established that endogenously synthesized prostacyclin (PGI(2)) could serve as a ligand for PPARdelta. In addition, the stable PGI(2) analog, carbaprostacyclin, and a synthetic PPARdelta agonist induced transactivation of endogenous PPARdelta in human colon carcinoma cells. We conclude from these observations that PPARdelta, similar to COX-2, is aberrantly expressed in colorectal tumors and that endogenous PPARdelta is transcriptionally responsive to PGI(2). However, the functional consequence of PPARdelta activation in colon carcinogenesis still needs to be determined.
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PMID:Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. 1108 69


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