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)

Polychlorinated biphenyls (PCBs), a group of persistent and widespread environmental pollutants, are considered to be immunotoxic, carcinogenic, and to induce apoptosis. However, the cellular mechanisms underlying the action of PCBs have not been established. Here, we investigated the effects of PCBs on the induction of cyclooxygenase-2 (COX-2). Among the several congeners examined, only 2,2',4,6,6'-pentachlorobiphenyl (PeCB) specifically increased the COX-2 promoter activity, and the levels of COX-2 mRNA and protein, and thereby enhanced prostaglandin E2 (PGE2) synthesis in Rat-1 cells. By conducting mutation analyses of the COX-2 promoter and its transcription factor, we found that the CRE site in COX-2 promoter and c-Jun are important for increased COX-2 promoter activity induced by 2,2',4,6,6'-PeCB. In addition, 2,2',4,6,6'-PeCB-stimulated COX-2 induction was reduced by the specific MAPK kinase (MEK) inhibitor, PD98059, and in p53-deficient cells, implying that COX-2 induction requires the activation of ERK1/2 MAPK and p53. The selective COX-2 inhibitor, NS-398, potentiated the 2,2',4,6,6'-PeCB-induced mitochondrial apoptotic pathway involved in Bcl-xL attenuation, cytochrome c release and the subsequent activation of caspase-3. Furthermore, the cell death was prevented by PGE2 treatment, suggesting that 2,2',4,6,6'-PeCB-induced apoptosis is restricted by prostaglandin upregulation by COX-2. Taken together, these results demonstrate that 2,2',4,6,6'-PeCB-induced COX-2 expression may be an important compensatory mechanism for abating 2,2',4,6,6'-PeCB toxicity.
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PMID:2,2',4,6,6'-Pentachlorobiphenyl-induced apoptosis is limited by cyclooxygenase-2 induction. 1552 91

Cyclooxygenase-2 (COX-2) has been implicated in a variety of human malignancies and, accordingly, COX-2 selective inhibitors are being investigated as important chemopreventive and therapeutic agents. How COX-2 overexpression results in tumorigenesis and how COX-2 selective agents mediate their chemopreventive effects are issues that remain poorly understood. Here we report that the tumor suppressor p53 upregulates COX-2 expression and that COX-2 can in turn inhibit p53-dependent transcription. Additionally, a COX-2-selective inhibitor potentiates p53-induced apoptosis, which also supports the notion that COX-2 activity appears to interfere with p53 function. Expression of exogenous COX-2 in p53 wild-type cells does not affect the cytoplasmic or nuclear levels of p53, suggesting that COX-2 may not affect p53 turnover or subcellular localization. We further demonstrate that endogenous COX-2 interacts with p53 and that COX-2 and p53 interactions are a physiologically relevant event. Thus, p53 upregulates COX-2 and COX-2 in turn appears to negatively affect p53 activity via mechanisms that could involve physical interactions between COX-2 and p53. Based on our results, we propose that p53-dependent upregulation and activation of COX-2 appear to be yet another novel mechanism by which p53 could abate its own growth-inhibitory and apoptotic effects.
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PMID:Cyclooxygenase-2 interacts with p53 and interferes with p53-dependent transcription and apoptosis. 1560 68

Evidence suggests that the angiogenic endothelium represents an important target through which celecoxib mediates in vivo antitumor effects. Nevertheless, the pharmacologic basis for celecoxib-caused growth inhibition in endothelial cells in vitro remains to be defined. Previously, we showed that celecoxib-induced apoptosis in PC-3 prostate cancer cells was mediated in part through the inhibition of 3-phosphoinositide-dependent kinase-1/Akt signaling. Our present findings show that celecoxib inhibits the growth of human umbilical vein endothelial cells (HUVEC) with pharmacologic profiles reminiscent of those of PC-3 cells. The underlying antiproliferative mechanism, however, may differ between these two cell types considering differences in the functional status of many tumor suppressors, including PTEN, p53, and retinoblastoma, all of which play integral roles in regulating cell cycle progression and survival. From a mechanistic perspective, the genomic integrity of the HUVEC system presents a vastly different intracellular context to examine how celecoxib acts to induce growth inhibition. Here, we obtain evidence that the antiproliferative effects of celecoxib and its close, cyclooxygenase-2-inactive analogue 4-[5-(2,5-dimethylphenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (DMC) in HUVECs at pharmacologically attainable concentrations (10-20 micromol/L) are attributable to the inhibition of phosphoinositide-dependent kinase-1/Akt signaling and cyclin-dependent kinase. Especially, celecoxib- and DMC-mediated G1 arrest is associated with attenuated retinoblastoma phosphorylation through the inhibition of multiple cyclin-dependent kinases (IC50, 10-35 micromol/L). Moreover, both celecoxib and DMC reduce neovascularization in the chicken chorioallantoic membrane assay, suggesting the involvement of a cyclooxygenase-2-independent mechanism in the in vivo antiangiogenic effects of celecoxib.
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PMID:Growth inhibitory effects of celecoxib in human umbilical vein endothelial cells are mediated through G1 arrest via multiple signaling mechanisms. 1563 61

Proton pump inhibitor (PPI) co-therapy is considered the best strategy in preventing gastrointestinal complications during non-steroidal anti-inflammatory drug (NSAID) treatment, but there is limited information available on its effect on gastric mucosal cell kinetics. To evaluate the effect of PPI co-therapy on gastric mucosa we investigated epithelial cell proliferation, apoptosis, epithelial growth factor receptor (EGFR) and p53 expression in patients on chronic non-selective NSAID or cyclooxygenase-2 selective inhibitor (COX-2) treatment. Gastric biopsies of the antrum were taken from 10-10 patients on chronic NSAID and COX-2, therapy prior and after 6 months PPI co-therapy, and 10 controls without any treatment. Cell proliferation, apoptosis, EGFR and p53 expression were measured by immunohistochemistry. At least 600 glandular epithel cells were encountered and results were expressed as % of total cells counted. We found increased cell proliferation in patients on chronic COX-2 but not on NSAID therapy. Patients on either NSAID or COX-2 therapy had an increased p53 and decreased EGFR expression. PPI therapy reversed not only the increased cell proliferation and p53 expression, but also the suppressed EGFR expression when administered as co-therapy. The fewer gastrointestinal side effects observed during chronic COX-2 therapy may partially be the result of the higher cell proliferation. This effect is not mediated by the EGFR pathway. PPI co-therapy normalizes the disturbed cell kinetics irrespective of NSAID treatment used.
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PMID:Proton pump inhibitor co-therapy normalizes the increased cell turnover of the gastric mucosa both in NSAID and selective COX-2 users. 1569 13

We have previously shown that p53 induces cyclooxygenase-2 (COX-2) expression and COX-2 inhibits p53- or genotoxic stress-induced apoptosis. However, the COX-2 effects have been demonstrated indirectly by the use of a selective inhibitor, NS-398, and the molecular mechanisms by which COX-2 inhibits apoptosis have not been identified. In the present study, we demonstrated that COX-2 inhibits genotoxic stress-induced apoptosis by using an adenoviral COX-2 overexpression system. In addition, we found that COX-2 regulates the transcription function of p53 as evidenced by suppression of p53 target gene induction by COX-2 cotransfection. Furthermore, COX-2 interacted with p53 in vitro and in vivo, which was inhibited by the treatment with NS-398. Taken together, these results suggest a novel function of COX-2 that inhibits DNA damage-induced apoptosis through direct regulation of p53 function.
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PMID:COX-2 regulates p53 activity and inhibits DNA damage-induced apoptosis. 1570 91

A role for cyclooxygenase-2 (COX-2) in the development and progression of various tumors has been identified. Selective COX-2 inhibitors produce anti-proliferative effects in various cancer cell lines that express COX-2. However, the mechanisms underlying anti-tumor effects are unclear. Furthermore, few studies have studied COX-2 expression in gynecological cancers, especially endometrial cancer. The current study had two goals. We investigated the correlation between COX-2 expression and clinicopathological factors of uterine endometrial cancer. We also investigated effects of treatment with etodolac, a selective COX-2 inhibitor, on the uterine endometrial cancer cell line TMG-L, which expresses COX-2. We conclusively confirmed expression of COX-2 mRNA and protein in endometrial cancer that exceeded levels of COX-2 seen in normal endometrium. However, no significant correlations were observed between COX-2 expression in endometrial cancer tumor samples and clinicopathological factors or disease-free survival rate of patients with endometrial cancer. Study of COX-2 inhibition of TMG-L cells showed that etodolac produced dose-dependent inhibition of cell proliferation through G1 phase cell-cycle arrest. Etodolac-induced cell-cycle arrest might be caused by increases in p53 and P21WAF1 protein expression. Production of basic-fibroblast growth factor (bFGF, a pro-angiogenesis factor) was inhibited by etodolac in a dose-dependent manner. Furthermore, telomerase activity was inhibited and expression of hTERT mRNA was significantly inhibited with etodolac, leading to the conclusion that anti-tumor effects of etodolac on TMG-L cells are due to inhibition of both angiogenesis and telomerase activity. These results strongly suggest that COX-2 inhibitors have potential as therapeutic (and possibly, chemopreventive) agents for endometrial cancers that overexpress COX-2.
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PMID:Expression of cyclooxygenase-2 in uterine endometrial cancer and anti-tumor effects of a selective COX-2 inhibitor. 1580 36

Barrett's esophagus (BE) represents the most serious histological consequence of gastroesophageal reflux disease (GERD) that develops in 5-10% of patients with GERD. Given that BE is the only known precursor to esophageal adenocarcinoma (EA), a systematic endoscopic biopsy protocol can detect EAs at an early stage. However, endoscopic and histopathological evaluation of BE are not adequate for effective screening of high risk patients. Therefore, molecular abnormalities associated with BE have been considered as surrogate markers and their use as such is proposed. Flow cytometry is the most useful adjunct to histology, and ploidy status of BE is an independent risk factor. Cyclin D1 overexpression is inversely correlated with survival in EA. C-erbB2 (+) patients have poorer prognosis. High plasma adenomatous polyposis coli levels correlate with reduced patient survival. p53 expression allows patient risk for EA stratification. Nuclear factor-kappaB overexpression inversely correlates with good response to adjuvant chemotherapy and radiotherapy in EA. Patients with cyclooxygenase-2 overexpression have reduced survival rates. Increased E-cadherin staining is associated with shorter survival in EA patients who received chemoradiotherapy. Finally, existing data cannot rule out a correlation between EA and colorectal tumors. Seventeen BE molecular alterations yielded noteworthy clinical implications. Apart from endoscopy and histology, these data allow for better risk stratification for patients with BE and for more efficient and timely therapeutic approaches.
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PMID:New molecular concepts of Barrett's esophagus: clinical implications and biomarkers. 1585 73

5-Fluorouracil (5-FU) is one of the widely used chemotherapeutic drugs targeting various cancers, but its chemo-resistance remains as a major obstacle in clinical settings. In the present study, HT-29 colon cancer cells were markedly sensitized to apoptosis by both 5-FU and genistein compared to the 5-FU treatment alone. There is an emerging evidence that genistein, soy-derived phytoestrogen, may have potential as a chemotherapeutic agent capable of inducing apoptosis or suppressing tumor promoting proteins such as cyclooxygenase-2 (COX-2). However, the precise mechanism of cellular cytotoxicity of genistein is not known. The present study focused on the correlation of AMPK and COX-2 in combined cytotoxicity of 5-FU and genistein, since AMPK is known as a primary cellular homeostasis regulator and a possible target molecule of cancer treatment, and COX-2 as cell proliferation and anti-apoptotic molecule. Our results demonstrated that the combination of 5-FU and genistein abolished the up-regulated state of COX-2 and prostaglandin secretion caused by 5-FU treatment in HT-29 colon cancer cells. These appear to be followed by the specific activation of AMPK and the up-regulation of p53, p21, and Bax by genistein. Under same conditions, the induction of Glut-1 by 5-FU was diminished by the combination treatment with 5-FU and genistein. Furthermore, the reactive oxygen species (ROS) was found as an upstream signal for AMPK activation by genistein. These results suggested that the combination of 5-FU and genistein exert a novel chemotherapeutic effect in colon cancers, and AMPK may be a novel regulatory molecule of COX-2 expression, further implying its involvement in cytotoxicity caused by genistein.
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PMID:Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathways. 1589 11

We examined the morphological, biochemical and molecular outcome of a nonspecific sulfhydryl reduction in cells, obtained by supplementation of N-acetyl-L-cysteine (NAC) in a 0.1-10 mM concentration range. In human normal primary keratinocytes and in colon and ovary carcinoma cells we obtained evidences for: (i) a dose-dependent inhibition of proliferation without toxicity or apoptosis; (ii) a transition from a proliferative mesenchymal morphology to cell-specific differentiated structures; (iii) a noticeable increase in cell-cell and cell-substratum junctions; (iv) a relocation of the oncogenic beta-catenin at the cell-cell junctions; (v) inhibition of microtubules aggregation; (vi) upregulation of differentiation-related genes including p53, heat shock protein 27 gene, N-myc downstream-regulated gene 1, E-cadherin, and downregulation of cyclooxygenase-2; (vii) inhibition of c-Src tyrosine kinase. In conclusion, a thiol reduction devoid of toxicity as that operated by NAC apparently leads to terminal differentiation of normal and cancer cells through a pleiade of converging mechanisms, many of which are targets of the recently developed differentiation therapy.
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PMID:Differentiation of normal and cancer cells induced by sulfhydryl reduction: biochemical and molecular mechanisms. 1592 May 36

Elevated cyclooxygenase-2 (COX-2) expression has been observed in various types of cancer. Induction of COX-2 expression has been reported to increase invasiveness and angiogenesis of tumours. While COX-2 overexpression has been repeatedly proven to promote tumor growth, little is known about what initiates its induction. There has been evidence to suggest that COX-2 expression is normally suppressed by wild-type p53 but not mutant p53, suggesting that loss of p53 function may result in the induction of COX-2 expression. Loss of p53 function is not only caused by gene mutation, but also through the overexpression of its negative regulator, so called human double minute 2 (hdm2). The aim of this study was to examine the correlation between COX-2 overexpression, p53 accumulation and HDM2 overexpression, as indications of p53 anomalies, and their relationship to clinicopathologic features of colorectal adenocarcinoma. Tumor tissues and the adjacent normal mucosa were obtained from 73 colorectal cancer patients who underwent curative resection at Maharaj Nakorn Chiang Mai Hospital. Protein levels of COX-2, p53 and HDM2 were determined by Western blot analysis. No normal colorectal tissues possessed detectable levels of COX-2, p53 or HDM2. In contrast, 38.3% (28 cases), 54.8% (40 cases) and 8.2% (6 cases) of tumour tissues were found to express COX-2, p53 and HDM2, respectively. Interestingly, there was a significantly positive relationship between COX-2 overexpression and p53 accumulation and/or HDM2 overexpression (P=0.007). Higher COX-2 overexpression was observed in p53-accumulated or HDM2 overexpressed-tumours (22/43 cases, 51.1%) in comparison to tumours with no evidence of p53 and HDM2 alterations (6/30 cases, 20%). The results obtained from this study indicate that overexpression of COX-2 is frequently associated with p53 protein accumulation and HDM2 overexpression, therefore the COX-2 overexpression observed in colorectal cancer cells may be partly due to the dysfunction of p53. Although mutation of p53 has been previously reported to be associated with COX-2 induction, to our knowledge, this is the first study to show the relationship between HDM2 overexpression and COX-2 overexpression.
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PMID:Expression of cyclooxygenase-2 in colorectal adenocarcinoma is associated with p53 accumulation and hdm2 overexpression. 1592 50


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