Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase-2 (COX-2) overexpression and mutations of p53 (a known COX-2 regulator) are inversely associated with microsatellite instability-high (MSI-H) and CpG island methylator phenotype (CIMP) characterized by extensive promoter methylation, is associated with MSI-H. However, no studies have comprehensively examined interrelations between COX-2, p53, MSI, and CIMP. Using MethyLight, we measured DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16/INK4A), CRABP1, MLH1, and NEUROG1] in relatively unbiased samples of 751 colorectal cancer cases obtained from two large prospective cohorts; 115 (15%) tumors were CIMP-high (> or = 4 of 5 methylated promoters), 251 (33%) were CIMP-low (1 to 3 methylated promoters), and the remaining 385 (51%) were CIMP-0 (no methylated promoters). CIMP-high tumors were much less frequent in COX-2+/p53+ tumors (4.6%) than in COX-2+/p53- tumors (19%; P < .0001), COX-2-/p53+ tumors (17%; P = .04), and COX-2-/p53- tumors (28%; P < .0001). In addition, COX-2+/p53+ tumors were significantly less common in MSI-H CIMP-high tumors (9.7%) than in non-MSI-H CIMP-low/CIMP-0 tumors (44-47%; P < .0001). In conclusion, COX-2 and p53 alterations were synergistically inversely correlated with both MSI-H and CIMP-high. Our data suggest that a combined analysis of COX-2 and p53 may be more useful for the molecular classification of colorectal cancer than either COX-2 or p53 analysis alone.
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PMID:Combined analysis of COX-2 and p53 expressions reveals synergistic inverse correlations with microsatellite instability and CpG island methylator phenotype in colorectal cancer. 1682 91

Esophageal cancer remains a highly lethal malignancy for which the genetic and proteomic events are poorly understood. Studies have reported dysregulated proteins in esophageal carcinoma; however, the magnitude of these changes remains largely uncharacterized. Little is known about alterations early in the neoplastic pathway. Using multiplex tissue immunoblotting, we quantified the expression of seven proteins in esophageal carcinogenesis. Regions of normal, dysplasia, and invasive carcinoma of the squamous esophagus in six patients were characterized. Pan-cytokeratin (CK) was essentially unchanged across the transition (0.96 in dysplasia and 0.69 in tumor). Expression levels of annexin 1, CK-4, and CK-14 were all decreased in dysplasia and tumor compared with normal (reference, 1.00): annexin 1, 0.30 in dysplasia and 0.15 in tumor; CK-4, 0.20 in dysplasia and 0.16 in tumor; and CK-14, 0.54 in dysplasia and 0.40 in tumor. Expression of two proteins was increased in dysplasia and tumor versus normal: cyclooxygenase-2, 1.35 in dysplasia and 2.32 in tumor and p53, 1.29 in dysplasia and 2.37 in tumor. Secreted protein, acidic and rich in cysteine, which is expressed in the adjacent stroma, was 1.56-fold higher in stroma underlying dysplasia and 6.20-fold increased in dysplastic stroma surrounding invasive tumor. These findings suggest that changes in protein expression can be detected during the transition to dysplasia and may be useful biomarkers.
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PMID:A multiplex tissue immunoblotting assay for proteomic profiling: a pilot study of the normal to tumor transition of esophageal squamous cell carcinoma. 1683 44

Cyclooxygenase-2 (COX-2) expression is up-regulated in transformed cells and in malignant tissues, including tumours of the head and neck, and it has prognostic significance in many types of cancer. COX-2 expression is suppressed by the wild-type but not by the mutant tumour suppressor gene TP53. The purpose of this study was to investigate the association between the expression of COX-2 and the clinical outcome in patients with oral and pharyngeal squamous cell carcinoma (SCC), and to examine its relationship to p53. Immunohistochemistry showed an elevated COX-2 expression in 88% (n = 57; strong 38, weak 19) of the 65 tumour samples. The staining intensity was not associated with patient or tumour characteristics, nor with the immuhistochemical expression of p53. Kaplan-Meier analysis showed no significant correlation between COX-2 expression and recurrence-free or overall survival, but a strong p53 expression was associated with a poor recurrence-free (p = 0.001, log-rank) and overall survival (p = 0.003). We conclude that, unlike strong p53 expression, COX-2 expression does not have prognostic significance in advanced oral and pharyngeal SCCs.
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PMID:Cyclooxygenase-2 expression in squamous cell carcinoma of the oral cavity and pharynx: association to p53 and clinical outcome. 1686 47

Cell lines that do not overexpress functional cyclooxygenase-2 are resistant to the normal plasma levels of celecoxib achieved following oral ingestion. Cell growth inhibition was demonstrated after 24 h exposure to 80 micromol/l celecoxib while significant death was not detected at concentrations below 120 micromol/l following 24 h exposure. This growth inhibition and death induction was identified to be independent of p53 and Hdm2 in these cells, despite wild-type p53 stabilization and Hdm2 diminution in some lines. Cell death induced by celecoxib was preceded by the generation of reactive oxygen species within 4 h of drug exposure. The precise mechanism of elicitation of reactive oxygen species in these cells remains to be elucidated, although it was found to be independent of p53 and c-Abl, while in vitro, celecoxib enhanced superoxide radical production by xanthine oxidase. Importantly, the failure of anti-oxidants to protect from death indicates that celecoxib induces death independently of reactive oxygen species and that reactive oxygen species generation may be an insufficient trigger of death in p53-deficient cells.
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PMID:Celecoxib can induce cell death independently of cyclooxygenase-2, p53, Mdm2, c-Abl and reactive oxygen species. 1691 6

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

Cyclooxygenase-2 (COX-2) is upregulated in many tumors including neuroblastoma, and its overexpression has been implicated in resistance to p53-dependent apoptosis. Although p53 is rarely mutated in neuroblastoma, the p53 protein is rendered inactive via several mechanisms including sequestration in the cytoplasm. Here, we show that COX inhibitors inhibit the growth of neuroblastoma and when combined with low doses of chemotherapy, exert synergistic effects on neuroblastoma cells. Following COX inhibitor treatment, HDM2, which targets p53 for ubiquitin-mediated degradation, is downregulated, resulting in an attenuation of p53 ubiquitination and an increase in p53 half-life. The level of HDM2 phosphorylation at ser166, which influences both HDM2 and p53 subcellular distribution, is markedly diminished in response to COX inhibitors and is associated with increased p53 nuclear localization. Combining COX inhibitors with low-dose chemotherapy potentiates apoptosis and p53 stability, nuclear localization, and activity. p53 knockdown by siRNA resulted in the rescue of COX-inhibitor-treated cells, indicating that COX inhibitor-induced apoptosis is, at least in part, p53-dependent. Taken together, these results provide the first evidence that COX inhibitors enhance chemosensitivity in neuroblastoma via downregulating HDM2 and augmenting p53 stability and nuclear accumulation.
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PMID:Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma. 1698 34

Intestinal metaplasia in Barrett's esophagus is a major risk factor for esophageal adenocarcinoma, a tumor whose incidence rate has more than tripled in the United States over the past 2 decades. Studies have identified a number of molecular abnormalities that may be involved in the progression from dysplasia to cancer in Barrett's esophagus, including altered expression of cadherins and catenins; inactivation of tumor-suppressor genes, such as p53, p21, p27, and p16; and increased activity of the enzymes cyclooxygenase-2 and inducible nitric oxide synthase. Studies on the role of Helicobacter pylori in the pathogenesis of intestinal metaplasia at the gastroesophageal junction have yielded contradictory results. It appears, however, that gastric infection with strains of H. pylori containing a cagA gene associated with cytotoxin expression may protect against the development of dysplasia and adenocarcinoma in Barrett's esophagus. The role of ablation therapy for Barrett's esophagus remains controversial, largely because thermal and photochemical ablative techniques often leave foci of intestinal metaplasia behind.
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PMID:Barrett's esophagus. 1702 71

Although many studies have revealed the association between cyclooxygenase-2 (COX-2) and carcinogenesis, the association between COX-2 and Hodgkin's lymphoma (HL) remains unknown. We examined the immunohistochemical expression of COX-2, p53, bcl-2, and Ki-67 in 33 patients with HL, and counted microvessels stained with CD34. Hodgkin and Reed - Sternberg (HRS) cells with COX-2 expression were scored as 0 = no staining; 1 = <25% of cells staining; 2 = 25-49%; 3 = 50-75%; and 4 = > or =75%. COX-2 expression was observed in 15 cases of classical HL. Nevertheless, neither accumulation of p53 nor bcl-2 expression was associated with COX-2 expression. The percentage of Ki-67 positive-HRS cells and microvessel density in COX-2 score groups 2-4 were significantly higher than those in score group 0, respectively. We show that COX-2 expression is associated with cell proliferation and angiogenesis in HL. These findings suggest that COX-2 may be a target for therapy in HL.
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PMID:Expression of cyclooxygenase-2 in Hodgkin's lymphoma: its role in cell proliferation and angiogenesis. 1706 99

Non-steroidal anti-inflammatory drugs are well known to induce apoptosis of cancer cells independent of their ability to inhibit cyclooxygenase-2, but the molecular mechanism for this effect has not yet been fully elucidated. The purpose of this study was to elucidate the potential signaling components underlying sulindac-induced apoptosis in human multiple myeloma (MM) cells. We found that sulindac induces apoptosis by promoting ROS generation, accompanied by opening of mitochondrial permeability transition pores, release of cytochrome c and apoptosis inducing factor from mitochondria, followed by caspase activation. Bcl-2 cleavage and down-regulation of the inhibitor of apoptosis proteins (IAPs) family including cIAP-1/2, XIAP, and survivin, occurred downstream of ROS production during sulindac-induced apoptosis. Forced expression of survivin and Bcl-2 blocked sulindac-induced apoptosis. Most importantly, sulindac-derived ROS activated p38 mitogen-activated protein kinase and p53. SB203580, a p38 mitogen-activated protein kinase inhibitor, and RNA inhibition of p53 inhibited the sulindac-induced apoptosis. Furthermore, p53, Bax, and Bak accumulated in mitochondria during sulindac-induced apoptosis. All of these events were significantly suppressed by SB203580. Our results demonstrate a novel mechanism of sulindac-induced apoptosis in human MM cells, namely, accumulation of p53, Bax, and Bak in mitochondria mediated by p38 MAPK activation downstream of ROS production.
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PMID:Sulindac-derived reactive oxygen species induce apoptosis of human multiple myeloma cells via p38 mitogen activated protein kinase-induced mitochondrial dysfunction. 1713 20

Sulindac sulfide and sulindac sulfone have demonstrated anti-neoplastic and chemo-preventive activity against various human tumors, but few studies have examined the relative effectiveness of these drugs against squamous cell carcinoma of the head and neck (SCCHN). These compounds are metabolites of the nonsteroidal anti-inflammatory drug sulindac and differ in their ability to inhibit cyclooxygenase-2 (COX-2) enzyme function. Sulindac sulfide (the sulindac metabolite with COX-2 inhibitory function) demonstrated strong cell growth inhibition as measured by MTT and growth assays in UM-SCC-1 and SCC-25 cells, while sulindac sulfone had only moderate effect. Growth inhibition by sulindac sulfide was associated with a significant increase in percent G cells and activation of caspase-3. Sulindac sulfide induced expression of p21wafl/cipl in a dose-dependent fashion, decreased cyclin D1 protein levels, and increased Rb hypophosphorylation. p21waf1/cip1 protein levels increased without a significant increase in wild-type p53, suggesting that sulindac sulfide induces a p53-independent pathway regulating p2lwafl/ciP1 protein levels in SCCHN. Sulindac sulfide also induced dose-dependent expression of PPAR-gamma. In contrast, sulindac sulfone did not significantly alter apoptosis, cell cycle distribution or G1 checkpoint protein expression at doses below 200 microM. These results demonstrate the differential activity of sulindac metabolites and support the hypothesis that sulindac sulfide induced perturbations in SCCHN cellular proliferation could be regulated both by p21waf1/cip1-dependent cytostatic and caspase-dependent cytotoxic pathways.
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PMID:Differential activity of sulindac metabolites against squamous cell carcinoma of the head and neck is mediated by p21waf1/cip1 induction and cell cycle inhibition. 1717 18


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