Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase-2 (COX-2) is not normally expressed in the human large intestine, but its levels are increased in the majority of human colorectal carcinomas. Here we investigate the regulation of constitutive COX-2 expression and prostaglandin production in human colorectal carcinoma cells. Both COX-2 mRNA and protein were expressed in well differentiated HCA-7, Moser, LS-174, and HT-29 cells, albeit at different levels. COX-2 expression was not detected in several poorly differentiated colon cancer cell lines including DLD-1. Transcriptional regulation played a key role for the expression of COX-2 in human colon carcinoma cells, and both the nuclear factor for interleukin-6 regulatory element and the cAMP-response element were responsible for regulation of COX-2 transcription. COX-2 mRNA was more stable in HCA-7 cells than in the other cell lines tested. Both transcriptional and post-transcriptional regulation of COX-2 involved the MAP kinase pathway. Modulation of the Akt/protein kinase B or Rho B signaling pathways altered the levels of COX-2 expression. Furthermore, COX-2 protein is degraded through ubiquitin proteolysis, and its half-life was approximately 3.5-8 h. HCA-7 cells produced significant quantities of prostaglandin E(2) and other prostaglandins. Moser and LS-174 cells also generated prostaglandins, but levels were significantly lower than that observed in HCA-7 cells.
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PMID:Regulation of constitutive cyclooxygenase-2 expression in colon carcinoma cells. 1093 Apr 1

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

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

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.
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PMID:Cholinergic receptor up-regulates COX-2 expression and prostaglandin E(2) production in colon cancer cells. 1102 34

We previously found (I. Shureiqi et al., Carcinogenesis (Lond.), 20: 1985-1995, 1999; I. Shureiqi et al, J. Natl. Cancer Inst., 92: 1136-1142, 2000) that (a) 15-lipoxygenase-1 (15-LOX-1) protein and its product 13-S-hydroxyoctadecadienoic acid (13-S-HODE) are decreased; and (b) nonsteroidal anti-inflammatory drug (NSAID)-induced 15-LOX-1 expression is critical to NSAID-induced apoptosis in colorectal cancer cells expressing cyclooxygenase-2 (COX-2). We used the NSAIDs sulindac sulfone (COX-2-independent) and NS-398 (a COX-2 inhibitor) to assess NSAID upregulation of 15-LOX-1 in relation to COX-2 inhibition during NSAID-induced apoptosis in the DLD-1 (COX-2-negative) colon cancer cell line. We found that: (a) NSAIDs up-regulated 15-LOX-1, which preceded apoptosis; and (b) 15-LOX-1 inhibition blocked NSAID-induced apoptosis, which was restored by 13-S-HODE but not by its parent, linoleic acid. NSAIDs can induce apoptosis in colon cancer cells via up-regulation of 15-LOX-1 in the absence of COX-2.
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PMID:15-Lipoxygenase-1 mediates nonsteroidal anti-inflammatory drug-induced apoptosis independently of cyclooxygenase-2 in colon cancer cells. 1115 77

To study the temporal expression of motile structures and protease activity during colon cancer cell invasion by heregulin-beta1 (HRG) and prostaglandin E2 (PGE2), we have developed a three-dimensional spatial model system. HRG and PGE2 each induced the formation of well-organized, three-dimensional structures with empty spaces in the center and stimulated the expression of urokinase plasminogen activator (uPA) with differential localization of membrane-bound uPA at the focal adhesion points and leading edges of the motile cells. A specific cyclooxygenase-2 inhibitor blocked the formation of three-dimensional luminal glandular structures induced by HRG but did not block those induced by PGE2. A specific antagonist of uPA receptor completely blocked the formation of these luminal glandular structures induced by PGE2 and HRG. These findings suggest that HRG-mediated increased invasiveness of colon cancer cells is augmented at least in part by induction of PGE2 and uPA, and this augmentation may involve the formation of three-dimensional invasive structures via the uPA pathway. In addition, the three-dimensional model system presented here may have a wider application to screen the effects of therapeutic compounds and biomolecules on different spatial aspects of colonic biology, including cell growth, motility, invasion, survival, and apoptosis.
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PMID:A three-dimensional and temporo-spatial model to study invasiveness of cancer cells by heregulin and prostaglandin E2. 1119 3

Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown cancer preventive activity in patients who took them frequently. These drugs can induce tumor cells to undergo apoptosis in vitro. NS398, a cyclooxygenase-2 (COX-2)-selective inhibitor, has been reported to cause apoptosis in cancer cell lines. Therefore, we examined its effect on 15 human colon cancer cell lines and investigated its mechanism of action. NS398 decreased cell viability in all of the cell lines. Tumor cells that expressed COX-2 were shown to be more sensitive to NS398 treatment. In three selected colon cancer cell lines, NS398-induced apoptosis was mediated by the release of cytochrome c from mitochondria and, consequently, by the activation of caspase-9 and caspase-3 and by the cleavage of poly(ADP-ribose) polymerase. In contrast, caspase-8 was not involved in NS398-induced apoptosis, which suggested that the cytochrome c pathway may play an important role in NS398-induced apoptosis in colon cancer cell lines. Therefore, the combination of NS398 with apoptosis-inducing drugs through cytochrome c-independent pathways may be warranted.
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PMID:Induction of apoptosis in colon cancer cells by cyclooxygenase-2 inhibitor NS398 through a cytochrome c-dependent pathway. 1130 52

Curcumin prevents colon cancer in rodent models. It inhibits lipid peroxidation and cyclooxygenase-2 (COX-2) expression and induces glutathione S-transferase (GST) enzymes. We tested the hypothesis that 14 days of dietary curcumin (2%) affects biomarkers relevant to cancer chemoprevention in the rat. Levels of inducible COX-2, as reflected by prostaglandin E(2) production by blood leukocytes, were measured ex vivo. Total GST activity and adducts of malondialdehyde with DNA (M(1)G), which reflect endogenous lipid peroxidation, were measured in colon mucosa, liver, and blood leukocytes. Curcumin and its metabolites were analyzed by high-performance liquid chromatography in plasma, and its pharmacokinetics were compared following a diet containing 2% curcumin versus intragastric (i.g.) administration of curcumin suspended in an amphiphilic solvent. The curcumin diet did not alter any of the markers in the blood but increased hepatic GST by 16% and decreased colon M(1)G levels by 36% when compared with controls. Administration of carbon tetrachloride during the treatment period increased colon M(1)G levels, and this increase was prevented by dietary curcumin. Dietary curcumin yielded low drug levels in the plasma, between 0 and 12 nM, whereas tissue concentrations of curcumin in liver and colon mucosa were 0.1--0.9 nmol/g and 0.2--1.8 micromol/g, respectively. In comparison with dietary administration, suspended curcumin given i.g. resulted in more curcumin in the plasma but much less in the colon mucosa. The results show that curcumin mixed with the diet achieves drug levels in the colon and liver sufficient to explain the pharmacological activities observed and suggest that this mode of administration may be preferable for the chemoprevention of colon cancer.
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PMID:Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels. 1135 Sep 17

Suppression of occurrence and advancement of premalignant lesions is important for cancer prevention. Our previous studies clarified that beta-catenin-accumulated crypts, independent of aberrant crypt foci (ACF), are probably direct precursors of colon cancers in rats. Here we investigated the effects of a selective cyclooxygenase-2 inhibitor, celecoxib, on the development of beta-catenin-accumulated crypts in comparison with those on ACF. Male F344 rats were divided into 4 groups. Groups 1 - 3 were administered azoxymethane (AOM) s.c. at a dose of 15 mg / kg body weight, once weekly for 3 weeks to induce beta-catenin-accumulated crypts. Groups 2 and 3 also received experimental diet containing celecoxib (500 and 1500 ppm, respectively) for 8 weeks, starting a week before the first dosing of AOM. At termination, the frequency and crypt multiplicity (number of crypts / lesion) of beta-catenin-accumulated crypts of groups 2 and 3 were significantly less than that of group 1. Furthermore, numbers of silver-stained nucleolar organizer regions (AgNORs) / nucleus in beta-catenin-accumulated crypts were also decreased by exposure to celecoxib. In this study, celecoxib had greater effects on the frequency and growth of beta-catenin-accumulated crypts than on those of ACF. These findings represent additional evidence that beta-catenin-accumulated crypts are premalignant lesions of colon cancer. The results also suggest that beta-catenin-accumulated crypts could be a novel target for evaluation of possible chemopreventive agents against colon carcino-genesis, and indicate that possible chemopreventive effects of celecoxib on the initial stage of colon carcinogenesis may be related to modulation of cell proliferation activity in such early lesions.
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PMID:Suppression of occurrence and advancement of beta-catenin-accumulated crypts, possible premalignant lesions of colon cancer, by selective cyclooxygenase-2 inhibitor, celecoxib. 1142 49

The gamma isoform of the peroxisome proliferator-activated receptor (PPARgamma) is a nuclear receptor that regulates adipocyte differentiation. Recently it has been shown to be expressed in human colonic mucosa and cancer, but its role in colon carcinogenesis and progression is still unclear. We demonstrate that activation of PPARgamma by ciglitazone (cig), a selective PPARgamma ligand, induces HT-29 human colon cancer cells to undergo apoptosis. Treatment with cig also down-regulates expression of cyclooxygenase-2 (COX-2) protein. Simultaneous exposure of cells to cig and 9-cis-retinoic acid (9-cis-RA), a ligand for retinoid X receptor, results in an increased apoptotic effect and increased inhibition of COX-2 expression, compared with cells treated with either cig or 9-cis-RA alone. As COX-2 is overexpressed in human colon cancer and has been implicated in augmenting invasiveness and tumorigenecity, the ability of PPARgamma activation to decrease COX-2 expression and induce apoptosis suggests that the PPARgamma pathway may be considered as a therapeutic target for colon cancer.
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PMID:Activation of the PPAR pathway induces apoptosis and COX-2 inhibition in HT-29 human colon cancer cells. 1153 58


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