Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of cyclooxygenase-2 (COX-2) is observed early in colon cancer. Treatments with COX-2-specific NSAIDs have been shown to reduce polyp size and polyp number in FAP patients with a predisposition to colorectal adenoma and cancer. However, the use of COX-2-specific NSAIDs in colon cancer patients has recently revealed increased cardiovascular risks. These harmful side effects may be the result of COX-dependent and/or COX-independent mechanisms. RNA interference (RNAi) is a method of post-transcriptional gene silencing intrinsic to cells. This study employed RNAi to specifically knockdown endogenous COX-2 expression in the HT-29 colon cancer cell line, and to observe the apoptotic response as well as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression levels. Following treatment with a COX-2 siRNA, we demonstrated a significant knockdown at the protein level of 57% as compared to a non-silencing siRNA control. Protein results were corroborated by concurrent decrease in COX-2 mRNA levels following the same treatment regimen. Despite previous studies using NSAID treatment to implicate COX-2 involvement in apoptosis, we did not observe any alteration in Bcl-2 expression and Caspase-3 activation following COX-2 knockdown in these cells. 15-PGDH, a physiological antagonist of COX-2 in its catabolism of PGE2, showed a modest but significant induction in response to COX-2 knockdown. The precise role of COX-2 in apoptosis and PGE2 regulation remains unclear; however, having shown that down-regulation of endogenous levels of COX-2 can be achieved in colon cancer by RNAi, this strategy should prove to be a valuable tool in revealing the specific function of COX-2 in tumourigenesis.
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PMID:Cyclooxygenase-2 knockdown by RNA interference in colon cancer. 1639 11

Visceral glomerular epithelial cells (GEC) are crucial for glomerular permselectivity and structural integrity in the kidney. The current study addressed the role of cyclooxygenase (COX)-2 and its product prostaglandin (PG) E2 in GEC survival. We generated a subclone of cultured rat GEC, which overexpress COX-2 in an inducible manner. When COX-2 was induced, GEC survived better in serum-deprived conditions. Induction of COX-2 was correlated with increased PGE2 generation, increased activation of extracellular signal-regulated kinase, decreased apoptosis, and increased cell proliferation. Rat GEC abundantly expressed the EP4 isoform of PGE2 receptor. Induction of COX-2 and addition of exogenous PGE2 both lead to decreased serum deprivation-induced apoptosis, which was accompanied by activation of the survival kinase Akt. Anti-apoptotic effect of COX-2 induction was reversed by the specific inhibitor of the EP4 receptor, L-161982. PGE2 also inhibited puromycin aminonucleoside-induced GEC apoptosis in vitro. Acute puromycin aminonucleoside nephrosis (PAN) is a rat model of GEC injury and proteinuria. In rats with PAN, glomerular apoptosis, quantified as caspase-3 activity, as well as urinary protein excretion were significantly increased, compared with control rats. Administration of L-161982 in rats with PAN further exacerbated caspase-3 activation and proteinuria. Thus COX-2 and its product PGE2 may have anti-apoptotic/protective effect on GEC via the EP4 receptor of PGE2.
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PMID:Prostaglandin E2 promotes cell survival of glomerular epithelial cells via the EP4 receptor. 1639 44

The causes of, and predisposing conditions for, increased congenital anomalies in embryos of experimental diabetic gestation are not fully identified. In the present study, some possible factors involved in diabetes-induced embryopathy are explored. The concentration of PGE2, the gene expression of cyclooxygenases (COX-1 and COX-2) and level of apoptosis (measured by caspase-3 activity) are assessed during organogenesis in the embryos of streptozotocin-induced diabetic rats. The concentrations of PGE2 in the embryos of diabetic rats were lower than controls, with the lowest values in malformed embryos and their associated membranes (yolk sacs). The pattern of change in PGE2 was similar in the embryos of the control and diabetic groups, which showed a steady decline between days 9 and 11 of gestation. These changes in PGE2 were accompanied by a small decrease in COX-1 expression in all embryos and associated membranes during the same gestational period. Expression of COX-2, which was below normal in diabetic embryos, decreased between days 9 and 11 of gestation in all groups. In the membranes of non-malformed embryos, COX-2 expression peaked on day 10 of gestation. It was found that there was little or no detectable COX-2 expression in the membranes of malformed embryos on day 9 of gestation and although its expression was detectable on the following days it was much lower than in the other groups. Caspase-3 activity increased substantially between days 9 and 11 of gestation. Embryos from the experimentally diabetic group showed higher activity than did controls, with the largest increases in the malformed embryos. It would appear that COX-2 expression and PGE2 concentration (in both embryo and associated membranes) play a significant role in organ formation. The data presented here suggest that an unhealthy placenta may be instrumental in the development of malformed embryos.
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PMID:Embryopathy in experimental diabetic gestation: assessment of PGE2 level, gene expression of cyclooxygenases and apoptosis. 1641 74

Pulmonary inflammation and parenchymal apoptosis are implicated in the pathogenesis of the acute lung injury, but the mechanisms of these reactions are still unclear. Because inhibition of the proinflammatory cyclo-oxygenase (COX)-2 enzyme action is proposed to be useful in various inflammatory lung injuries, we decided to investigate the expression of COX-2 and the possible beneficial effects of its inhibition on pulmonary inflammation and apoptosis in surfactant-depleted lungs. The injury was induced in 2-mo-old rats by repeated lung lavage to remove alveolar surfactant. Eight of these rats were pretreated with a specific COX-2 inhibitor, NS-398. All rats, including control rats without lung lavage, were ventilated with 60% oxygen for 5 h, and the lungs were then studied histologically for tissue injury and with DNA nick-end labeling, cleaved caspase-3 immunohistochemistry, and electron microscopy for apoptotic cell death. Lung tissue myeloperoxidase activity and the expression of COX-2 protein and concentration of prostaglandin E2 were additionally analyzed. Lung lavage increased pulmonary neutrophil migration, histologic injury, and the occurrence of epithelial apoptosis. In contrast, expression of COX-2 and amount of PGE2 were significantly lower in surfactant-depleted lungs than controls. Pretreatment with the COX-2 inhibitor further increased the migration of neutrophils and occurrence of epithelial apoptosis in the surfactant-depleted lungs, compared with nontreated insulted lungs. These results suggest that specific inhibitors of COX-2 should be used cautiously in association with surfactant-deficient lung injuries.
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PMID:Inhibition of COX-2 aggravates neutrophil migration and pneumocyte apoptosis in surfactant-depleted rat lungs. 1649 81

Sepsis induced by exposure to lipopolysaccharide (LPS) can be life-threatening and lead to multiple-organ dysfunction. Sepsis-associated cardiac dysfunction is a primary cause of mortality. The response of isolated cardiac myocytes to LPS exposure is poorly understood. Cultured neonatal rat ventricular cardiomyocytes were used to evaluate the response to LPS exposure. Other authors have reported that LPS exposure at doses sufficient to induce tumor necrosis factor alpha (TNF-alpha) production and apoptosis in adult cardiomyocytes do not induce apoptosis in neonatal cardiomyocytes. We therefore hypothesized that neonatal cardiomyocytes have innate protective mechanisms that protect from septic damage. Cultured neonatal rat ventricular cardiomyocytes were stimulated by exposure to LPS for varying lengths of time. NFkappaB signaling pathways, TNF-alpha production, and Akt activation were monitored. We also assessed the induction of apoptosis in these cells by monitoring caspase-3 activity. LPS rapidly stimulates nuclear translocation of NFkappaB and Akt activation. TNF-alpha production is also stimulated. However, high doses of LPS are unable to induce apoptosis in these cells, and protection is not a function of Akt activation. LPS treatment also stimulated the levels of cyclooxygenase-2 and the production of downstream metabolites, specifically PGE2 and 15deoxyDelta12-14PGJ2 (15dPGJ2). Specific inhibition of cyclooxygenase-2 activity induced apoptosis in the presence of LPS, whereas direct exposure to 15dPGJ2 at pharmacological levels induced apoptosis. Neonatal rat ventricular cardiomyocytes have innate protective mechanisms that prevent apoptotic cell death after LPS exposure. Metabolic products of arachidonic acid metabolized by the cyclooxygenase pathway can be potentially apoptotic or antiapoptotic. The balance of these products within these cells may define the cellular response to LPS exposure.
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PMID:The response of neonatal rat ventricular myocytes to lipopolysaccharide-induced stress. 1668 21

Prostaglandin E(2) (PGE(2)) is bone-anabolic, i.e. stimulates bone formation and increases bone mass. In this study, we explored possible intracellular mechanisms of its increase of osteogenic cells in rat bone marrow. Adherent rat bone marrow cells were counted after 12-48 h or cultured for 21 days and mineralized nodules were counted. Also, apoptosis of marrow cells was measured after in vivo PGE(2) injection. PGE(2) (100 nM) increased 2-3 fold the number of adherent BMSC, an effect which was mediated via binding the EP(4) receptor since it was mimicked by forskolin and 11-deoxy-prostaglandin E(1) (PGE(1)) and was blocked by DDA and L-161982 (EP(4) antagonist). PGE(2) stimulated sphingosine kinase (SPK) activity since its effects were blocked by DMS (SPK inhibitor) and mimicked by SPP (SPK product). PGE(2) reduced the activity of caspase-3 and -8 in BMSC and their inhibitors increased BMSC number and nodule formation. In vivo, PGE(2) prevented the increase in the apoptosis of bone marrow cells caused by indomethacin. We propose that PGE(2) exerts an anti-apoptotic effect on BMSC, thereby increasing their number and subsequent osteoblastic differentiation. Such an effect could explain how PGE(2) stimulates bone formation in vivo.
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PMID:Prostaglandin E2 (PGE2) increases the number of rat bone marrow osteogenic stromal cells (BMSC) via binding the EP4 receptor, activating sphingosine kinase and inhibiting caspase activity. 1689 Apr 16

Adipocytes can function as endocrine cells secreting a variety of adipocytokines including tumor necrosis factor (TNF)-alpha. Treatment of cultured mouse 3T3-L1 preadipocytes with TNF-alpha induced apoptosis, as was evident from increases in nuclear condensation and caspase-3 activity, but differentiated adipocytes during the maturation phase showed resistance to apoptosis by TNF-alpha. Antioxidants effectively reduced TNF-alpha-induced apoptosis in preadipocytes, indicating the involvement of reactive oxygen species. Exposure of preadipocytes to calcium ionophore A23187 reduced TNF-alpha-induced apoptosis, which was accompanied by increased production of prostaglandins (PGs) E2 and PGF 2alpha. TNF-alpha preferentially promoted gene expression of cyclooxygenase (COX)-2 without affecting that of COX-1. Consistently, NS-398, a COX-2 inhibitor, stimulated TNF-alpha-induced apoptosis, which was reversed by exogenous PGE2 and PGF 2alpha. These results indicate that endogenous PGE2 and PGF 2alpha synthesized by preadipocytes through the induction of COX-2 can serve as anti-apoptotic factors against apoptosis by TNF-alpha.
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PMID:Endogenous prostaglandins E2 and F 2alpha serve as an anti-apoptotic factor against apoptosis induced by tumor necrosis factor-alpha in mouse 3T3-L1 preadipocytes. 1696 Mar 84

Cyclooxygenase-2 (COX-2) activity has been implicated in the pathogenesis of cerebral ischemia. To determine whether COX-2 activity within the neuron itself exacerbates hypoxic neuronal injury, neuron-enriched cultures were subjected to anoxia. Treatment with COX-2 selective antagonists decreased cell death. Neurons cultured from homozygous COX-2 gene disrupted mice were resistant to hypoxia compared to those of heterozygotes. Infection of primary neurons with AAV expressing COX-2 exacerbated cell death compared to neurons infected with enhanced green fluorescent protein (EGFP) control vector. Addition of PGE2, PGD2 or PGF2 alpha to the medium exacerbated injury, suggesting that the deleterious effects of COX-2 overexpression in hypoxia could be mediated by direct receptor mediated effects of prostaglandins. Overexpression of COX-2 did not increase expression of cyclin D1 or phosphoretinoblastoma protein (pRb), or cleavage of caspase 3 suggesting that this cell cycle mechanism does not mediate COX-2 toxicity in this model.
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PMID:Neuronal cyclooxygenase-2 activity and prostaglandins PGE2, PGD2, and PGF2 alpha exacerbate hypoxic neuronal injury in neuron-enriched primary culture. 1776 46

Primary cultures of human lung cells can serve as a model system to study the mechanisms underlying the effects of irritants in air and to get a deeper insight into the (patho)physiological roles of the xenobiotic detoxification systems. For 99 human lung cancer cases the culture duration for bronchial epithelium and peripheral lung cells (PLC) are given in term of generations and weeks. Using this system, we investigated whether and how prostaglandins (PG) modify multidrug resistance related protein (MRP) function in normal human lung cells. PGF2alpha had no effect on MRP function, whereas PGE2 induced MRP activity in cultured NHBECs. The transport activity study of MRP in NHBEC, PLC, and A549 under the effect of exogenously supplied PGF2alpha (10 microM, 1 day) using single cell fluorimetry revealed no alteration in transport activity of MRP. PG concentrations were within the physiological range. COX I and II inhibitors indomethacin (5, 10 microM) and celecoxib (5, 10 microM) could substantially decrease the transport activity of MRP in NHBEC, PLC, and A549 in 1- and 4-day trials. Prostaglandin E2 did not change cadmium-induced caspase 3/7 activation in NHBECs and had no own effect on caspase 3/7 activity. Cadmium chloride (5, 10 microM) was an effective inducer of caspase 3/7 activation in NHBECs with a fivefold and ninefold rise of activity. In primary human lung cells arachidonic acid activates MRP transport function only in primary epithelial lung cells by prostaglandin E2 but not by F2alpha mediated pathways and this effect needs some time to develop.
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PMID:Arachidonic acid pathway activates multidrug resistance related protein in cultured human lung cells. 1794 74

Prostaglandin E(2) (PGE(2)) is a potent inhibitor of ionizing radiation (IR)-induced cell death. Exposure of colon cancer cells to IR leads to increased CUGBP2 expression. Therefore, we tested the hypothesis that PGE(2) radioprotects colon cancer cells by inhibiting CUGBP2 expression. Exposure of HCT-116 cells to gamma-IR (0-12 Gy) resulted in a dose-dependent reduction in cell growth and an increase in the G(2)-M phase of the cell cycle. Western blot analyses demonstrated increased levels of activated caspase 9 and caspase 3. In addition, whereas Bax expression is increased, that of Bcl-2 and Bcl-x(L) was reduced. Further analyses demonstrated increased activation of Chk1 and Chk2 kinases, coupled with higher levels of nuclear cyclin B1 and Cdc2. Pretreatment with PGE(2) suppressed the activation of caspase 3 and caspase 7 and inhibited Bax expression. In addition, PGE(2) treatment restored growth and colony formation to control levels. IR significantly upregulated the expression of CUGBP2 in the cells, which was suppressed when cells were pretreated with PGE(2). Ectopic overexpression of CUGBP2 also induced apoptosis. Furthermore, it reversed the PGE(2)-mediated protection from IR-induced mitotic catastrophe. Furthermore, there was an increase in nuclear localization of cyclin B1 and Cdc2 coupled with increased phosphorylation of p53, Chk1, Chk2, and Cdc25c proteins. Cell cycle analysis also demonstrated increased G(2)-M transition. In contrast, siRNA-mediated suppression of CUGBP2 expression restored normal cell cycle progression and decreased IR-induced apoptosis. Taken together, these data demonstrate that PGE(2) protects colon cancer cells from IR-induced mitotic catastrophe in part through suppression of CUGBP2 expression.
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PMID:CUGBP2 downregulation by prostaglandin E2 protects colon cancer cells from radiation-induced mitotic catastrophe. 1832 84


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