UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of U937 cells with mono(2-ethylhexyl)phthalate (MEHP) for 20 h led to a dose-dependent loss of cell viability, assessed by propidium iodide (PI) staining with fluorescent activated cell sorting (FACS) analysis. The cytotoxic behavior of MEHP is attributed to the induction of apoptosis. MEHP induced activation of caspase-3, internucleosomal DNA fragmentation and the morphological features of nuclear apoptosis. Analysis with LightCycler quantitative RT-PCR demonstrated the decrease of bcl-2 and increase of bax mRNA levels. Peroxisome proliferator-activated receptor (PPAR) gamma antagonists, bisphenol A diglycidyl ether (BADGE) and GW9662, significantly inhibited the MEHP-induced caspase-3 activity and apoptotic nuclear morphological changes. Furthermore, a PPARgamma ligand, rosiglitazone synergized the MEHP-induced caspase-3 activity. These results suggest that MEHP can induce apoptosis in U937 cells through modulation of the balance of bcl-2/bax in part by PPARgamma activation.
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PMID:Induction of apoptosis by mono(2-ethylhexyl)phthalate (MEHP) in U937 cells. 1292 54

Cyclooxygenase-2 (COX-2) expression and certain growth hormones, such as gastrin, have been related to gastric carcinogenesis, but little is known about the factors that enhance this COX-2 expression and whether specific blockade of this enzyme has any influence on tumor growth and progression. Our objective was to determine the influence of a specific COX-2 inhibitor, rofecoxib (Vioxx), on serum and tumor levels of gastrin and its precursor, progastrin, as well as on tumor gene expression of COX-2, peroxisome proliferator-activated receptor gamma (PPARgamma), and apoptosis-related proteins (Bax and Bcl-2, caspase-3, and survivin). Twenty-four gastric cancer (GC) patients entered this study and were examined twice, once before and then following a 14-day treatment with Vioxx at a dose of 25 mg twice daily. For comparison, 48 age- and sex-matched healthy controls and 24 similarly matched Helicobacter pylori (Hp)-positive subjects were enrolled and treated with Vioxx as GC patients. Serum levels of anti-Hp and anti-CagA antibodies as well as IL-8 and TNF-alpha were measured by enzyme-linked immunosorbent assay (ELISA), while serum and tumor contents of progastrin and amidated gastrin were determined by specific RIA. Tumor gene and protein expressions of COX-2, PPARgamma, Bax and Bcl-2, caspase-3, and survivin were determined by RT-PCR and western blot. The overall Hp and CagA seropositivity in 24 GC patients was significantly higher (82% and 47%) than in 48 controls (61% and 22%) but not in 24 Hp-infected subjects (100% and 38%). Serum IL-8 and TNF-alpha values were significantly higher in GC patients than in controls without GC or Hp-infected controls. Median serum progastrin and gastrin levels were found to be significantly higher in GC than in controls without GC and in Hp-positive subjects. Treatment of GC patients with Vioxx resulted in a significant decrease in plasma and tumor contents of both progastrin and gastrin, and this was accompanied by the increment in tumor expression of COX-2, PPARy, Bax, and caspase-3 with a concomitant reduction in Bcl-2 and survivin expression. We conclude that: (1) GC patients show significantly higher Hp and CagA seropositivity than age- and sex-matched controls, but not Hp-positive subjects, indicating that infection with cytotoxic Hp is linked to GC. (2) Serum progastrin and gastrin levels are significantly higher in GC patients than in matched controls, confirming that both gastrins may be implicated in gastric carcinogenesis. (3) GC patients exhibit significantly higher levels of IL-8 and TNF-alpha than non-GC controls and Hp-positive subjects, probably reflecting more widespread gastritis in GC. (4) COX-2, PPARgamma, Bcl-2, and survivin were overexpressed in gastric tumor, but the inhibition of COX-2 activity by Vioxx resulted in a significant reduction in serum and tumor levels of progastrin and gastrin and serum IL-8 and TNF-alpha levels, suggesting that gastrin and proinflammatory cytokines could mediate the up-regulation of COX-2 in gastric cancerogenesis. (5) Vioxx also enhanced expression of COX-2, PPARy, Bax, and caspase-3, while inhibiting the expression of Bcl-2 and survivin, suggesting that COX-2 blockade might be useful in chemoprevention against gastric cancer possibly due to enhancement of the PPARy- and proapoptotic proteins-dependent apoptosis and the reduction in progastrin/gastrin-induced promotion of tumor growth.
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PMID:Influence of COX-2 inhibition by rofecoxib on serum and tumor progastrin and gastrin levels and expression of PPARgamma and apoptosis-related proteins in gastric cancer patients. 1462 49

Mast cells produce chemical mediators, including histamine and arachidonate metabolites such as prostaglandin D(2) (PGD(2)) after antigen stimulation. Cyclopentenone prostaglandins of the J series, prostaglandin J(2) (PGJ(2)) and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), are thought to be derivatives of PGD(2). In this study, the biphasic effects of the PGJ(2) and 15d-PGJ(2) on proliferation and apoptosis in rat basophilic leukemia cells (RBL-2H3), a tumor analog of mast cells, were examined. At low concentrations, 1 or 3 microM PGJ(2) and 15d-PGJ(2) induced cell proliferation, respectively. At high concentrations (10-30 microM) both the inhibition of viability and decrease in histamine content in RBL-2H3 cells were dose dependent. These effects were independent of the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARgamma), since troglitazone, an agonist of PPARgamma did not cause any effects in RBL-2H3 cells. Cell death induced by PGJ(2) and 15d-PGJ(2) was the result of apoptotic processes, since RBL-2H3 cells treated with 30 microM of the prostaglandins had condensed nuclei, DNA fragmentation and increase in activities of caspase-3 and -9. Moreover, PGJ(2) or 15d-PGJ(2)-induced apoptotic effects were prevented by the caspase inhibitor, z-VAD-fmk. In conclusion, the PGJ(2) or 15d-PGJ(2)-induced apoptosis in RBL-2H3 cells occurs mainly via mitochondrial pathways instead of by PPARgamma-dependent mechanisms.
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PMID:The biphasic effects of cyclopentenone prostaglandins, prostaglandin J(2) and 15-deoxy-Delta(12,14)-prostaglandin J(2) on proliferation and apoptosis in rat basophilic leukemia (RBL-2H3) cells. 1501 41

Senescence-associated changes in the prostate are believed to play an important role in the genesis of prostate cancer. In order to provide further information on how aging increases the prostate susceptibility to cancer, we examined the pattern of cyclooxygenase (COX)-2 expression and the concomitant alterations in prostaglandin E(2) (PGE(2)) synthesis in the prostate glands of 4-, 10-, 50- and 100-week-old Fischer 344 rats. This was carried out in the prostatic areas where hormone-induced tumors arise, namely the periurethral ducts of the dorsolateral prostate (DLP). Age-associated changes were also evaluated for pro- and anti-apoptotic factors linked to COX-2 signaling and known to be involved in the normal development of the prostate gland as well as in carcinogenesis. COX-2 expression was increased in the DLP in an age-dependent manner where senescent rats had >3-4-fold higher COX-2 mRNA and protein levels than their juvenile counterparts (P<0.05). The age-related changes in COX-2 were accompanied by a similar up-regulation in the PGE(2) synthesis. Evaluation of mediators of apoptotic signaling showed a significant (P<0.05) decline in the expression levels of the pro-apoptotic BAX (>6-fold) and peroxisome proliferator-activated receptor gamma (>3-fold) and in caspase-3 activity (>2-fold) and an up-regulation of the anti-apoptotic Bcl(2) (>8-fold), PKCalpha (>2-fold) and pAkt (>4-fold) in the 100-week-old rats versus the 4-week-old animals. There was an approximately 15-fold age-dependent decrease in the pro-apoptotic ratio BAX:Bcl(2) and an increase in the anti-apoptotic variable PKCalpha(*)Bcl(2)/BAX in the senescent rats compared with the juvenile ones. These results suggest that increased COX-2 expression can be linked to the decline in the pro-apoptotic signaling in the prostate gland during aging. Subsequently, COX-2 inhibitors can be considered as a promising class of agents to attenuate the increased cell survival and, hence, protect against tumorigenesis in the aging prostate.
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PMID:Age-associated changes in the expression pattern of cyclooxygenase-2 and related apoptotic markers in the cancer susceptible region of rat prostate. 1511 12

In this study, we investigated the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on 1-methyl-4-phenylpyridinium (MPP(+))-induced cell death in PC12 cells. Coincubation of PC12 cells with indomethacin, ibuprofen, ketoprofen, or diclofenac, but not aspirin or N-[2-(cyclohexyloxy)-4-nitrophenyl]methanosulfonamide (NS-398), significantly potentiated the MPP(+)-induced cell death. In contrast, these NSAIDs had no effect on rotenone-induced cell death. The potentiating actions of these NSAIDs were not suppressed by treatment with phenyl-N-butyl-nitrone, a radical scavenger; N-acetyl-l-cysteine, an antioxidant; Ac-DEVD-CHO, a selective caspase-3 inhibitor; or 2-chloro-5-nitro-N-phenylbenzamide (GW9662), a selective antagonist of peroxisome proliferator-activated receptor gamma. Furthermore, we observed that DNA fragmentation, which is one of the hallmarks of apoptosis, was not induced by coincubation with MPP(+) and NSAIDs. We confirmed that coincubation of PC12 cells with 30 microM MPP(+) and 100 microM indomethacin, ibuprofen, ketoprofen, or diclofenac led to a significant increase in the accumulation of intracellular MPP(+) compared with incubation with 30 microM MPP(+) alone. In addition, these NSAIDs markedly reduced the efflux of MPP(+) from PC12 cells. (3-(3-(2-(7-Chloro-2-quinolinyl) ethenyl) phenyl ((3-dimethyl amino-3oxo-propyl) thio) methyl) propanoic acid (MK 571), which is an inhibitor of multidrug resistance proteins (MRPs), mimicked the NSAIDs-induced effects, increasing cell toxicity and promoting the accumulation of MPP(+). Moreover, some types of MRPs' mRNA were detected in PC12 cells. These results suggest that some NSAIDs might cause a significant increase in the intracellular accumulation of MPP(+) via the suppression of reverse transport by the blockade of MRP, resulting in the potentiation of MPP(+)-induced cell death.
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PMID:Nonsteroidal anti-inflammatory drugs potentiate 1-methyl-4-phenylpyridinium (MPP+)-induced cell death by promoting the intracellular accumulation of MPP+ in PC12 cells. 1513 Dec 42

Peroxisome proliferator-activated receptor gamma (PPARgamma) has emerged recently as an important participant in the resolution of inflammation by conveying signals that lead to mitogen-activated protein kinase (MAPK) cascade activation. In this study, we report that PPARgamma activation leading to the impedance of P. gingivalis lipopolysaccharide (LPS) inhibitory effect on salivary mucin synthesis requires epidermal growth factor receptor (EGFR) participation. We show that activation of PPARgamma with a specific agonist, ciglitazone, prevents the LPS-induced reduction in mucin synthesis, and the effect is reflected in a marked decrease in apoptosis, caspase-3 activity and NO generation. The impedance by ciglitazone of the LPS-induced reduction in mucin synthesis was countered (up to 68.9%) in a dose-dependent fashion by a specific inhibitor of EGFR kinase, PD153035, as well as wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K). Moreover, the inhibitory effect of ciglitazone on the LPS-induced reduction in mucin synthesis and upregulation in apoptosis, caspase-3 activity, and NO generation was blunted by a selective inhibitor of tyrosine kinase Src, PP2, responsible for ligand-independent EGFR transactivation. These findings indicate that PPARgamma activation leading to the suppression of P. gingivalis LPS inhibition of salivary mucin synthesis involves Src kinase-dependent EGFR transactivation.
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PMID:Src kinase-dependent epidermal growth factor receptor transactivation in PPARgamma ligand-induced suppression of Porphyromonas gingivalis interference with salivary mucin synthesis. 1518 49

Despite new approaches, treatment options for malignant gliomas are still limited, calling for further development of therapeutic strategies. The peroxisome proliferator-activated receptor (PPAR)gamma, a member of the nuclear hormone receptor family, represents a possible new target for neoplastic therapies. Synthetic PPARgamma agonists were developed and are already in clinical use for the treatment of type II diabetes, since PPARgamma plays a crucial role in lipid metabolism and regulation of insulin sensitivity. Beyond these metabolic effects, PPARgamma agonists exhibit antineoplastic effects in various malignant tumor cells. Here, we investigated the antineoplastic effects of the nonthiazolidinedione tyrosine-based PPARgamma ligand (S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}ethylamino)benzoic acid methyl ester (GW7845) in rat and human glioma cells. GW7845 reduced cellular viability of rat C6 glioma and human glioma cells in a time-dependent manner. Analysis of GW7845-treated tumor cells revealed induction of apoptotic cell death as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and cleaved caspase-3 activation. Furthermore, GW7845 reduced proliferation of C6 glioma cells as measured by Ki-67 immunore-activity. There was also a reduction of migration and invasion, assessed by Boyden chamber and spheroid experiments. Together, these data indicate that the PPARgamma agonist GW7845 may be of potential use in treatment of malignant gliomas.
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PMID:The nonthiazolidinedione tyrosine-based peroxisome proliferator-activated receptor gamma ligand GW7845 induces apoptosis and limits migration and invasion of rat and human glioma cells. 1566 44

We previously reported that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the most potent agonist for peroxisome proliferator-activated receptor gamma (PPAR gamma), induces apoptosis of human chondrosarcoma cell line OUMS-27. The current study aimed to explore the mechanism of 15d-PGJ(2)-induced apoptosis and inhibition of cell proliferation in OUMS-27 cells. The preliminary results of cDNA microarray analysis showed the down-regulation of anti-apoptotic Bcl-xL and up-regulation of pro-apoptotic Bax in the process of 15d-PGJ(2)-induced apoptosis. These changes were further confirmed at mRNA and protein levels by RT-PCR and Western blot analysis, respectively. Among cyclin-dependent kinase inhibitors, p21 was induced and up-regulated by 15d-PGJ(2), but p16 and p27 were not changed, suggesting that the involvement of p21 in inhibition of cell proliferation. Activation of caspase-3 by 15d-PGJ(2) was partly, but not completely, blocked by PPAR gamma antagonist (GW9662) suggesting the 15d-PGJ(2) exerted its effect by PPAR gamma-dependent and -independent pathways. Interestingly, immunohistochemical study on human chondrosarcoma samples revealed that Bcl-xL is frequently expressed by tumor cells. The results of the current study suggest that the potential ability of 15d-PGJ(2) in regulation of cell cycle and inhibition of Bcl-xL expression might be beneficial in the development of novel pharmacological agents for chondrosarcoma.
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PMID:Suppression of chondrosarcoma cells by 15-deoxy-Delta 12,14-prostaglandin J2 is associated with altered expression of Bax/Bcl-xL and p21. 1569 58

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor important in fat metabolism and is emerging as an important regulator of immunity and inflammation. We previously demonstrated that normal and malignant B lineage cells express PPARgamma and die by apoptosis after PPARgamma agonist exposure. In this study, we used the WEHI-231 mouse B lymphoma and normal mouse spleen B lymphocytes to elucidate the mechanism of PPARgamma agonist-induced apoptosis, and to determine whether an apoptosis rescue mechanism exists. In WEHI-231 cells, the natural PPARgamma agonist 15-deoxy-Delta(12,14)-PGJ(2) and the synthetic PPARgamma agonist ciglitazone induced activation of caspase 3 and caspase 9, a decrease in mitochondrial membrane potential, and caused cleavage of the caspase substrate poly(ADP-ribose) polymerase. We next tested whether CD40, whose engagement delivers a potent prosurvival signal for B cells, could protect B cells from PPARgamma agonist-induced apoptosis. CD40 engagement with CD40L significantly blunted the ability of PPARgamma agonists to induce apoptosis of B lymphocytes and prevented the inhibition of NF-kappaB mobilization by 15-deoxy-Delta(12,14)-PGJ(2) and ciglitazone. Interestingly, PPARgamma agonists induced an increase in IkappaBalpha and IkappaBbeta protein levels, which was prevented with CD40 engagement. The rescue mechanism induced by CD40 engagement was dependent on NF-kappaB, as an NF-kappaB inhibitor prevented rescue. Apoptosis induction by PPARgamma ligands may be important for immune regulation by killing B lymphocytes as a rapid means to dampen inflammation. Moreover, the ability of PPARgamma agonists to kill malignant B lineage cells has implications for their use as anti-B lymphoma agents.
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PMID:CD40 engagement prevents peroxisome proliferator-activated receptor gamma agonist-induced apoptosis of B lymphocytes and B lymphoma cells by an NF-kappaB-dependent mechanism. 1577 64

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a nuclear hormone receptor that is involved in a wide range of cellular processes. Although it is known that PPAR-gamma plays an important role in cell cycle control, inflammation, apoptotic cell death, and other cellular processes, the role of PPAR-gamma in the normal and pathological function of growth plate chondrocytes has not been investigated. The purpose of this study was to determine if PPARs are expressed in growth plate chondrocytes and to describe the biological effect of PPAR activation in these cells. The results demonstrate the presence of three PPAR isoforms (alpha, delta, and gamma) in growth plate cartilage. Activation of PPAR-gamma by ciglitazone in growth plate chondrocytes inhibits T(3) induced terminal differentiation and promotes apoptosis through increased levels of caspase 3/7 activity and decreased expression of the anti-apoptotic protein Bcl-2.
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PMID:Expression and activation of peroxisome proliferator-activated receptors in growth plate chondrocytes. 1587 53

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