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)

The immune regulation of phytohemagglutinin (PHA) and concanavalin A (Con A) mitogen responses by prostaglandin (PG)-producing suppressor monocytes was examined in 57 patients with colorectal cancer and 55 normal individuals. The blood lymphocyte responses to either PHA or Con A were significantly depressed in 74% of patients compared to normal controls. The mean PHA response for the patients was significantly lower than that for controls (17,649 versus 25,549 cpm, P = 0.02), while the mean Con A response for the patients was also depressed but not as significantly (13,551 versus 18,623 cpm, P = 0.09). The depression of immune competence was greatest in older patients and those with metastatic disease. The addition of indomethacin (1 microgram/ml) to cell cultures of both patients and normal individuals enhanced the mitogen response, suggesting that PGE-producing suppressor cells were operative in both groups. Among the patient group, however, a differential modulation of the immune response by indomethacin was observed. Thus, the addition of indomethacin restored the PHA response in patients almost to normal levels, while the Con A increase was less pronounced. Even after indomethacin treatment, the Con A proliferative response by lymphocytes was significantly depressed in patients as compared to controls (P = 0.002). To prove that indomethacin was blocking excessive PG production by suppressor monocytes in colon cancer patients, we directly measured PGE2 production by peripheral blood mononuclear cells (PBMCs) using a radioimmunoassay. PBMCs from the patients produced significantly greater amounts of PGE2 compared to controls (10.1 versus 5.1 ng/ml, P = 0.0001). This comparison was still significant after adjustment for age and sex. The increased PGE2 production appeared to be selective, since the levels of two other arachidonic acid metabolites, PGF1 alpha and thromboxane B2, were the same or less than control levels. PG-mediated immune suppression of mitogenesis thus appears to be abnormally increased in colon cancer patients, particularly for the PHA response. This abnormality was partially corrected in vitro by incubation of the PBMCs with indomethacin, a prostaglandin synthetase inhibitor.
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PMID:Prostaglandin E2-mediated suppression of cellular immunity in colon cancer patients. 622 53

Treatment of nontransformed rat intestinal crypt epithelial IEC-6 cells with tetradecanoyl phorbol acetate (TPA) + calcium ionophore (A23187) induces both the synthesis of prostacyclin and the expression of the TIS10/PGS-2 gene, a primary response gene encoding a second form of prostaglandin synthase (PGS). In addition to pharmacological induction by TPA + A23187, TIS10/PGS-2 message is also induced by the inflammatory cytokine interleukin 1-beta (IL-1 beta). Transforming growth factor beta 1 (TGF-beta), a potent cytokine known to modulate a variety of biological responses, does not by itself induce either prostanoid accumulation or TIS10/PGS-2 gene expression. TGF-beta does, however, augment both induced prostacyclin accumulation and the induced synthesis and accumulation of TIS10/PGS-2 protein and message in IEC-6 cells. TGF-beta concentrations in the range of 0.1-1.0 ng/ml (4.0-40 pM) maximally augment accumulation of TIS10/PGS-2 message. In contrast, dexamethasone attenuates prostacyclin production, TIS10/PGS-2 protein accumulation, and TIS10/PGS-2 message induction in IEC-6 cells. These results suggest that steroids and cytokines such as TGF-beta may (i) modulate intestinal epithelial cell growth and differentiation and (ii) influence gastrointestinal diseases such as gastric ulcers and colon cancer by modulating eicosanoid production.
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PMID:TGF-beta 1 augments expression of the TIS10/prostaglandin synthase-2 gene in intestinal epithelial cells. 778 83

Nonsteroidal antiinflammatory drugs (NSAIDs) have considerable potential as chemopreventive agents for colorectal cancer. Recent case-control drug surveillance and large cohort studies found that patients with regular aspirin use had a reduced incidence of colorectal cancer and/or decreased death rate from this disease. Several different NSAIDs reduce formation of both colon adenomatous polyps (the precursor lesion of colon cancer) and cancers in experimental animals given known carcinogens. Perhaps most convincing are reports that the NSAID sulindac promotes regression and inhibits recurrence of adenomatous colon polyps in patients with adenomatous polyposis coli. The best characterized pharmacologic effect of the NSAIDs is their reduction of prostaglandin synthesis by inhibiting prostaglandin synthetase PGE2, which catalyzes the formation of prostaglandin precursors from arachidonic acid. Several lines of evidence are contrary to the concept that inhibition of prostaglandin synthesis is central to the NSAIDs' chemopreventive effects. Relatively high levels of prostaglandins have been reported to inhibit tumor cell growth both in vivo and in vitro, and to inhibit differentiation in some tumor cell lines. We evaluated comparative chemopreventive effects on colon tumor formation in an azoxymethane (AOM)-induced colon carcinogenesis rat model using the NSAIDs piroxicam, sulindac, and sulindac sulfone, a metabolite of sulindac which lacks the anti-prostaglandin synthetase activity typically associated with NSAID-induced gastrointestinal toxicities. The results demonstrate that sulindac sulfone, a compound lacking anti-prostaglandin synthetase activity, inhibits AOM-induced colon cancer in rats. Substantial dose-dependent reductions in both tumor burden and tumor multiplicity were observed in the sulindac sulfone-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase? 853 96

Both the sulfide and sulfone metabolites of sulindac, a nonsteroidal anti-inflammatory drug, display anticarcinogenic effects in experimental models. Sulindac sulfide inhibits cyclooxygenase (COX) enzyme activities and has been reported to suppress ras-dependent signaling. However, the mechanisms by which sulindac sulfone suppresses cancer growth are not as defined. We studied the effects of these sulindac metabolites in human colon cancer-derived Caco-2 cells that have been transfected with an activated K-ras oncogene. Stable transfected clones expressed high levels of COX-2 mRNA and protein, compared with parental cells. K-ras-transfected cells formed tumors more quickly when injected into severe combined immunodeficiency disease mice than parental cells, and this tumorigenesis was suppressed by treatment with sulindac. Sulindac sulfone inhibited COX-2 protein expression, which resulted in a decrease in prostaglandin synthase E2 production. Sulindac sulfide had little effect on COX-2 in this model, but did suppress prostaglandin synthase E2 production, presumably by inhibiting COX enzyme activity. These data indicate that the sulfide and sulfone derivatives of sulindac exert COX-dependent effects by distinct mechanisms.
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PMID:Sulindac sulfone inhibits K-ras-dependent cyclooxygenase-2 expression in human colon cancer cells. 1111 42

Cyclooxygenase (COX)-2, the inducible prostaglandin synthase, is overexpressed in cancer and chronic inflammatory diseases. Post-transcriptional regulation of COX-2 mRNA is important in controlling the expression of the COX-2 gene. Here, we report that leptomycin B (LMB), a specific inhibitor of the nuclear export factor CRM1 potently inhibits the stabilization of COX-2 mRNA in MDA-MB-231 human mammary cancer cells. However, COX-2 promoter-driven reporter gene expression is not inhibited by LMB, suggesting that LMB acts at the post-transcriptional level. Subcellular fractionation experiments indicate that LMB inhibited the time-dependent export of COX-2 mRNA into the membrane-bound polysomal compartment at the endoplasmic reticulum. LMB suppressed COX-2 expression by interleukin-1beta in HT-29 human colon cancer cells and in human umbilical vein endothelial cells but had no effect on COX-2 expression induced by Escherichia coli lipopolysaccharide in monocytic THP-1 cells. These data suggest that the nuclear export of COX-2 mRNA may be rate-liming in a cell-specific manner. LMB may be useful to control COX-2 expression in various human diseases in which COX-2 plays a pathogenetic role.
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PMID:Leptomycin B, an inhibitor of the nuclear export receptor CRM1, inhibits COX-2 expression. 1246 43

Cyclooxygenase (COX)-2, an inducible isoform of prostaglandin synthetase, has been reported to be a key molecular target of colon cancer prevention by nonsteroidal anti-inflammatory drugs. Recently, it has been shown that Helicobacter pylori (H. pylori) could induce COX-2 together with inflammatory cytokines. Although human hyperplastic gastric polyps disappeared or decreased in number and size after eradication of H. pylori, the mechanisms in this step, especially the roles of COX-2, have not been yet elucidated. The aims of the present study were to examine the expression and localization of COX-2 in human hyperplastic gastric polyps immunohistochemically. Twelve specimens of human hyperplastic gastric polyps were obtained from endoscopic polypectomy. The expression of the COX-2 protein was immunohistochemically examined on formalin-fixed and paraffin-embedded tissue sections using an anti-COX-2 antibody and an avidin-biotin complex method. Cells expressing COX-2 were further immunohistochemically identified using a specific antibody against macrophages (CD68), and myofibroblasts (alpha-smooth muscle actin). Immunoreactive COX-2 was predominantly and strongly expressed in interstitial cells in the sub-epithelial layer of 10 hyperplastic polyps. Semi-quantitative analysis revealed a significant increase in COX-2 expression in interstitial cells. The staining pattern of macrophages and myofibroblasts partly corresponded to that observed for COX-2 in hyperplastic gastric polyps. These results suggest that COX-2 in mesenchymal cells induced by H. pylori may play an important role in the tumorigenesis of human hyperplastic gastric polyps.
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PMID:Expression of cyclooxygenase-2 in human hyperplastic gastric polyps. 1458 2

Cyclooxygenase-2 (COX-2), an inducible prostaglandin G/H synthase, is overexpressed in several human cancers, including colon cancer, and therefore the potential ability of a selective COX-2 inhibitor, etoricoxib, is considered in the prevention of the 1,2-dimethyl hydrazine (DMH)-induced colon carcinogenesis in the rat model. DMH was injected s.c. for 6 weeks, whereas etoricoxib was fed orally to the rats on a daily basis. The results showed that DMH produced a very high number of multiple plaque lesions (MPLs), putative neoplastic biomarkers, localized throughout the colon, whereas considerable regression was observed with etoricoxib treatment. In addition, the etoricoxib group was the only group that exhibited very few of these lesions. Histopathological analysis revealed extreme dysplasia, a few adenomas, and other carcinogenic changes in the DMH group, which are distinctly absent in the etoricoxib-treated group. COX-2 was also seen to be highly expressed following DMH treatment. The DMH treatment caused very few apoptotic cells, as determined by the TUNEL assay of the colonic mucosa in paraffin sections whose number greatly increased following etoricoxib treatment. Because all these changes were clearly reversed by etoricoxib in DMH-treated animals, and the use of etoricoxib alone did not produce a neoplastic effect per se, it appears that etoricoxib, a selective COX-2 inhibitor, might be a safe and potentially chemopreventive agent in colon cancer.
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PMID:The cyclooxygenase-2 inhibitor etoricoxib is a potent chemopreventive agent of colon carcinogenesis in the rat model. 1939 53

The discovery of an inducible form of prostaglandin synthase initiated a reexamination of the biochemical pathways for ligand-induced prostaglandin synthesis. As a result, new pharmaceutical agents with potential activity against pain, fever, chronic and acute inflammation, cardiovascular disorders, and colon cancer have been developed and are currently under intense investigation. Careful biochemical and pharmacologic studies of the differences between the constitutive and inducible prostaglandin synthase enzymes have suggested a previously unexpected mechanism for some of the therapeutic effects of aspirin. Identification of a new phospholipase, and recognition of its role in mast cell prostaglandin production and in transcellular prostaglandin synthesis, have identified additional potential targets for pharmacologic intervention in inflammation and other prostaglandin-mediated disorders.
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PMID:Recent progress in the cellular and molecular biology of prostaglandin synthesis. 2123 25

Elevated expression of the prostaglandin synthase cyclooxygenase-2 (COX-2) is commonly observed in many chronic inflammatory diseases and cancer. However, the mechanisms allowing for pathogenic COX-2 overexpression are largely unknown. The gene for COX-2 (PTGS2) carries a common single-nucleotide polymorphism (SNP) at position 8473 (T8473C), in exon 10 that is associated with diseases in which COX-2 overexpression is a contributing factor. We demonstrate that the T8473C SNP resides within a region that targets COX-2 mRNA for degradation through microRNA-mediated regulation. miR-542-3p was identified to bind transcripts derived from the 8473T allele and promote mRNA decay. By contrast, the presence of the variant 8473C allele interfered with miR-542-3p binding, allowing for mRNA stabilization, and this effect was rescued using a mutated miR-542-3p at the respective 8473 site. Colon cancer cells and tissue displayed COX-2 mRNA levels that were dependent on T8473C allele dosage, and allele-specific expression of COX-2 was observed to be a contributing factor promoting COX-2 overexpression. These findings provide a novel molecular explanation underlying disease susceptibility associated with COX-2 T8473C SNP, and identify it as a potential marker for identifying cancer patients best served through selective COX-2 inhibition.
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PMID:A common single-nucleotide polymorphism in cyclooxygenase-2 disrupts microRNA-mediated regulation. 2182 7

Colon cancer growth requires growth-promoting interactions between malignant colonocytes and stromal cells. Epidermal growth factor receptors (EGFR) are expressed on colonocytes and many stromal cells. Furthermore, EGFR is required for efficient tumorigenesis in experimental colon cancer models. To dissect the cell-specific role of EGFR, we manipulated receptor function on stromal cells and cancer cells. To assess the role of stromal EGFR, HCT116 human colon cancer cells were implanted into immunodeficient mice expressing dominant negative (DN) Egfr(Velvet/+) or Egfr(+/+). To assess the role of cancer cell EGFR, HCT116 transfectants expressing inducible DN-Egfr were implanted into immunodeficient mice. To dissect EGFR signals in vitro, we examined colon cancer cells in monoculture or in cocultures with fibroblasts for EGFR transactivation and prostaglandin synthase 2 (PTGS2) induction. EGFR signals were determined by blotting, immunostaining and real-time PCR. Tumor xenografts in Egfr(Velvet/+) mice were significantly smaller than tumors in Egfr(+/+) mice, with decreased proliferation (Ki67) and increased apoptosis (cleaved caspase-3) in cancer cells and decreased stromal blood vessels. Mouse stromal transforming growth factor alpha (TGFA), amphiregulin (AREG), PTGS2 and Il1b and interleukin-1 receptor 1 (Il1r1) transcripts and cancer cell beta catenin (CTNNB1) and cyclin D1 (CCND1) were significantly lower in tumors obtained from Egfr(Velvet/+) mice. DN-EGFR HCT116 transfectants also formed significantly smaller tumors with reduced mouse Areg, Ptgs2, Il1b and Il1r1 transcripts. Coculture increased Caco-2 phospho-active ERBB (pERBB2), whereas DN-EGFR in Caco-2 cells suppressed fibroblast PTGS2 and prostaglandin E2 (PGE2). In monoculture, interleukin 1 beta (IL1B) transactivated EGFR in HCT116 cells. Stromal cell and colonocyte EGFRs are required for robust EGFR signals and efficient tumor growth, which involve EGFR-interleukin-1 crosstalk.
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PMID:Both stromal cell and colonocyte epidermal growth factor receptors control HCT116 colon cancer cell growth in tumor xenografts. 2279 16


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