Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of cyclooxygenase-2 (COX2) by non-steroidal anti-inflammatory drugs (NSAID) is known to suppress skin carcinogenesis. It was further suggested that inhibition of COX2-derived prostaglandins by NSAIDs could reduce levels of putative endogenous ligands of peroxisome proliferator-activated receptor-beta (PPARbeta), and these ligands could potentiate tumorigenesis. However, it is currently unclear whether ligand activation of PPARbeta either inhibits or potentiates carcinogenesis. The present studies were designed to examine the mechanism of NSAID-mediated chemoprevention in skin, and, in particular, to determine the role of PPARbeta in this process. A two-stage skin carcinogenicity bioassay was performed using wild-type and PPARbeta-null mice that were fed either a control diet or one containing 0.32 g sulindac/kg diet. Significant inhibition of chemically induced skin carcinogenesis was observed in both wild-type and PPARbeta-null mice, and this was associated with a marked decrease in the concentration of skin prostaglandins including PGE(2) and PGI(2). Results from these studies demonstrate that inhibition of COX2 by dietary sulindac in mouse skin can effectively inhibit chemically induced skin carcinogenesis, and suggest that the mechanism underlying this chemopreventive effect is independent of PPARbeta. Additionally, results from these studies do not support the hypothesis that ligand activation of PPARbeta by COX-derived metabolites potentiates chemically induced skin carcinogenesis.
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PMID:Inhibition of chemically induced skin carcinogenesis by sulindac is independent of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta). 1641 76

Cyclooxygenase-2 (COX-2) is an inducible enzyme that regulates prostaglandin synthesis and is overexpressed at sites of inflammation and in several epithelial cancers. A causal link for COX-2 in epithelial tumorigenesis was shown in genetically manipulated animal models of colon and breast carcinoma. Studies have elucidated the regulation of COX-2 expression and have identified EP receptors through which prostanoids exert their biological effects. Mechanistic studies indicated that COX-2 is involved in apoptosis resistance, angiogenesis, and tumor cell invasiveness, which appear to contribute to its effects in tumorigenesis. Furthermore, forced COX-2 expression has been shown to suppress apoptosis by modulating the level of death receptor 5 (DR5) and this effect was reversed by a COX inhibitor. COX enzymes are targets for cancer prevention as shown by the observation that nonselective COX and selective COX-2 inhibitors have been reported to effectively prevent experimental colon cancer and can regress colorectal polyps in patients with familial adenomatous polyposis. This review will focus on the role of COX-2 as a target for the prevention and treatment of human colorectal cancer.
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PMID:Targeting cyclooxygenase-2 for prevention and therapy of colorectal cancer. 1668 27

Overexpression of cyclooxygenase-2 (COX-2) is generally considered to promote tumorigenesis. To investigate a potential role of COX-2 in osteosarcoma, we overexpressed COX-2 in human osteosarcoma cells. Saos-2 cells deficient in COX-2 expression were retrovirally transduced or stably transfected with murine COX-2 cDNA. Functional expression of COX-2 was confirmed by Northern and Western analyses and prostaglandin production. Overexpression of COX-2 reduced cell numbers by 50% to 70% compared with controls. Decreased proliferation in COX-2-overexpressing cells was associated with cell cycle prolongation in G(2)-M. Apoptosis, measured by both Annexin V binding assay and terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining, was increased in cells overexpressing COX-2, and the increase was not reversed by treatment with NS-398, indicating that the effects were not mediated by prostaglandins. Retroviral COX-2 overexpression in two other human osteosarcoma cell lines, U2OS and TE85, also decreased cell viability. However, in the human colon carcinoma HCT-116 cell line, which is deficient in COX-2, retroviral overexpression of COX-2, at similar efficiency as in Saos-2 cells, increased resistance to apoptosis. Reactive oxygen species (ROS), measured by flow cytometry, were increased by COX-2 overexpression in Saos-2 cells but not in HCT-116 cells. Inhibition of peroxidase activity, but not of COX activity, blocked the ROS increase. Antioxidants blocked the increase in ROS and the increase in apoptosis due to COX-2 overexpression in Saos-2 cells. Our results suggest that (a) COX-2 overexpression in osteosarcoma cells may increase resistance to tumorigenesis by increasing ROS to levels that decrease cell viability and (b) the effects of COX-2 overexpression are cell type/tissue dependent.
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PMID:Overexpression of COX-2 in human osteosarcoma cells decreases proliferation and increases apoptosis. 1681 39

Cyclooxygenase-2 (COX-2) has been implicated in the development of gastrointestinal malignancies. The aim of the present study was to determine COX-2 expression/activity throughout stages of experimental and human pancreatic neoplasia. COX-2 immunohistochemistry was performed in pancreata of hamsters subjected to the carcinogen N-nitrosobis-(2-oxopropyl)amine (BOP) and in human pancreatic tumors. COX-2 activity was determined by prostaglandin E2 assay in tumor versus matched normal pancreatic tissues. The activity of the COX inhibitor sulindac was tested in the PC-1 hamster pancreatic cancer model. COX-2 expression was elevated in all pancreatic intraepithelial neoplasias (PanINs) and adenocarcinomas. In BOP-treated hamsters, there were significant progressive elevations in COX-2 expression throughout pancreatic tumorigenesis. In human samples, peak COX-2 expression occurred in PanIN2 lesions and remained moderately elevated in PanIN3 and adenocarcinoma tissues. COX-2 activity was significantly elevated in hamster and human pancreatic cancers compared to pair-matched normal pancreas. Furthermore, hamster pancreatic tumor engraftment/formation in the PC-1 hamster pancreatic cancer model was reduced 4.9-fold by oral administration of sulindac. Increased COX-2 expression is an early event in pancreatic carcinogeneses. The BOP-induced hamster carcinogenesis model is a representative model used to study the role of COX-2 in well-differentiated pancreatic tumorigenesis. COX inhibitors may have a role in preventing tumor engraftment/formation.
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PMID:Cyclooxygenase-2 expression in hamster and human pancreatic neoplasia. 1682 89

Colorectal cancer is a major cause of mortality and whilst up to 80% of sporadic colorectal tumours are considered preventable, trends toward increasing obesity suggest the potential for a further increase in its worldwide incidence. Novel methods of colorectal cancer prevention and therapy are therefore of considerable importance. Non-steroidal anti-inflammatory drugs (NSAIDs) are chemopreventive against colorectal cancer, mainly through their inhibitory effects on the cyclooxygenase isoform COX-2. COX enzymes represent the committed step in prostaglandin biosynthesis and it is predominantly increased COX-2-mediated prostaglandin-E2 (PGE2) production that has a strong association with colorectal neoplasia, by promoting cell survival, cell growth, migration, invasion and angiogenesis. COX-1 and COX-2 inhibition by traditional NSAIDs (for example, aspirin) although chemopreventive have some side effects due to the role of COX-1 in maintaining the integrity of the gastric mucosa. Interestingly, the use of COX-2 selective NSAIDs has also shown promise in the prevention/treatment of colorectal cancer while having a reduced impact on the gastric mucosa. However, the prolonged use of high dose COX-2 selective inhibitors is associated with a risk of cardiovascular side effects. Whilst COX-2 inhibitors may still represent viable adjuvants to current colorectal cancer therapy, there is an urgent need to further our understanding of the downstream mechanisms by which PGE2 promotes tumorigenesis and hence identify safer, more effective strategies for the prevention of colorectal cancer. In particular, PGE2 synthases and E-prostanoid receptors (EP1-4) have recently attracted considerable interest in this area. It is hoped that at the appropriate stage, selective (and possibly combinatorial) inhibition of the synthesis and signalling of those prostaglandins most highly associated with colorectal tumorigenesis, such as PGE2, may have advantages over COX-2 selective inhibition and therefore represent more suitable targets for long-term chemoprevention. Furthermore, as COX-2 is found to be overexpressed in cancers such as breast, gastric, lung and pancreatic, these investigations may also have broad implications for the prevention/treatment of a number of other malignancies.
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PMID:Mediators of PGE2 synthesis and signalling downstream of COX-2 represent potential targets for the prevention/treatment of colorectal cancer. 1685 32

Cyclooxygenase-2 (COX-2) is antiapoptotic and is implicated in tumorigenesis. Recent reports, however, have also ascribed a proapoptotic action to inducible COX-2. We show here for the first time that a stilbene, resveratrol, induces nuclear accumulation of COX-2 protein in human breast cancer MCF-7 and MDA-MB-231 cell cultures. The induction of COX-2 accumulation by resveratrol is mitogen-activated protein kinase (MAPK; extracellular signal-regulated kinase 1/2)- and activator protein 1- dependent. Nuclear COX-2 in resveratrol-treated cells colocalizes with Ser(15)-phosphorylated p53 and with p300, a coactivator for p53-dependent gene expression. The interaction of COX-2, p53, and p300, as well as resveratrol-induced apoptosis, was inhibited by a MAPK activation inhibitor, PD98059. A specific inhibitor of COX-2, NS398, and small interfering RNA knockdown of COX-2 were associated with reduced p53 phosphorylation and consequent decrease in p53-dependent apoptosis in resveratrol-treated cells. We conclude that nuclear accumulation of COX-2 can be induced by resveratrol and that the COX has a novel intranuclear colocalization with Ser(15)-phosphorylated p53 and p300, which facilitates apoptosis in resveratrol-treated breast cancer cells.
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PMID:Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells. 1692 24

Many human cancers exhibit elevated prostaglandin (PG) levels due to upregulation of cyclooxygenase-2 (COX-2), a key enzyme in eicosanoid biosynthesis. COX-2 over-expression has been observed in about 40% of cases of invasive breast carcinoma and at a higher frequency in preinvasive ductal carcinoma in situ tumors, Extensive pharmacologic and genetic evidence implicates COX enzymes in neoplasia. Epidemiologic analyses demonstrate a protective effect of COX-inhibiting nonsteroidal anti-inflammatory drugs with respect to human cancer. Complementary experimental studies have established that both conventional nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors suppress mammary tumor formation in rodent breast cancer models. Furthermore, knocking out Cox-2 reduces mammary tumorigenesis and angiogenesis, and, conversely, transgenic COX-2 over-expression induces tumor formation. The utility of COX/PG signaling as a target for chemoprevention has been established by randomized controlled clinical trials. However, these studies also identified increased cardiovascular risk associated with use of selective COX-2 inhibitors. Thus, current efforts are directed toward identifying safer approaches to antagonizing COX/PG signaling for cancer prevention and treatment, with a particular focus on PGE2 regulation and signaling, because PGE2 is a key pro-tumorigenic prostanoid.
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PMID:Inflammation and breast cancer. Cyclooxygenase/prostaglandin signaling and breast cancer. 1764 Mar 94

The study objective was to determine the prognostic value of assessment of staining of p53 and bcl-2 in a well-selected group of serous ovarian carcinomas. Immunohistochemical detection was used to identify both p53 and bcl-2 positive tumors. One hundred thirty-two tumors were analyzed for positivity of staining, grade of staining intensity, and for p53 alone, percent expression rates. These were analyzed alongside traditional clinicopathologic parameters for their ability to predict overall survival (OS), disease-free survival (DFS), and response to chemotherapy (CR). Univariate COX analysis revealed percent p53 expression (P = 0.012) and p53 grade (P = 0.01) to be significant predictors of DFS. Neither the p53 nor bcl-2 measurement parameters were found significant for OS or prediction of CR. On multivariate analysis, incorporating clinicopathologic parameters, p53 parameters did not retain independent significance for any outcome measure. As in primary reported studies, bcl-2 was not found to be of clear independent prognostic value in this group of ovarian tumors. If mutation of p53 and its consequent overexpression is an early event in ovarian tumorigenesis, then p53 assessment may prove useful prognostically in the assessment of either low-grade ovarian carcinomas, as a possible indicator for progression, or in early-stage ovarian tumors, as a marker of tumor aggression or likelihood of recurrence. p53 analysis of a larger group of stage I ovarian tumors would be desirable to further explain the potential association with DFS.
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PMID:P53 and bcl-2 assessment in serous ovarian carcinoma. 1833 6

Bak is a pro-apoptotic gene, which plays an important role in the multi-step process of gastrointestinal tumorigenesis. We hypothesized that downregulation of Bak expression in normal enterocytes will result in a transformed phenotype. The nontumorigenic intestinal epithelial cell line (IEC18) was transfected with the vector pMV12-AS-bak (encoding anti-sense bak). Three clones, with Bak protein levels similar to those seen in colon cancer cell lines and significantly lower than those found in the parental cells, were further evaluated. The three clones proliferated faster, demonstrated anchorage-independent growth in soft agar and a higher saturation density and plating efficiency. Furthermore, when injected into nude mice, these cells generated tumors after approximately 2-3 weeks. The cells were more resistant to the induction of apoptosis by sulindac sulfide and sulindac sulfone but more sensitive to COX 2 inhibitors (celecoxib and nimesulide). The levels of p16, cyclin D1 and COX 2 were higher in the three transformed clones. In summary,downregulation of Bak expression in normal enterocytes contributes to abnormal growth and tumorigenesis. COX 2 inhibitors may serve as important agents in the prevention and treatment of CRC as they only inhibit the growth of malignant cells.
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PMID:Malignant transformation of normal enterocytes following downregulation of Bak expression. 1834 38

The inducible cyclooxygenase isoform (COX-2) is associated with inflammation, tumorigenesis, as well as with physiological events. Despite efforts deployed in order to understand the biology of this multi-faceted enzyme, much remains to be understood. Nucleobindin (Nuc), a ubiquitous Ca(2+)-binding protein, possesses a putative COX-binding domain. In this study, we investigated its expression and subcellular localization in human neutrophils, its affinity for COX-2 as well as its possible impact on PGE(2) biosynthesis. Complementary subcellular localization approaches including nitrogen cavitation coupled to Percoll fractionation, immunofluorescence, confocal and electron microscopy collectively placed Nuc, COX-2, and all of the main enzymes involved in prostanoid synthesis, in the Golgi apparatus and endoplasmic reticulum of human neutrophils. Immunoprecipitation experiments indicated a high affinity between Nuc and COX-2. Addition of human recombinant (hr) Nuc to purified hrCOX-2 dose-dependently caused an increase in PGE(2) biosynthesis in response to arachidonic acid. Co-incubation of Nuc with COX-2-expressing neutrophil lysates also increased their capacity to produce PGE(2). Moreover, neutrophil transfection with hrNuc specifically enhanced PGE(2) biosynthesis. Together, these results identify a COX-2-associated protein which may have an impact in prostanoid biosynthesis.
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PMID:Nucleobindin co-localizes and associates with cyclooxygenase (COX)-2 in human neutrophils. 1849 1


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