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)

Expression and function of the TRAIL apoptotic pathway was investigated in normal and malignant breast epithelial cells. Glutathione-S-transferase (GST)-TRAIL extracellular domain fusion proteins were produced to analyze TRAIL-induced apoptosis. Only GST-TRAIL constructs containing regions homologous to the Fas self-association and ligand binding domains could induce apoptosis. GST-TRAIL induced significant (>90%) apoptosis in just one of eight normal and one of eight malignant breast cell lines. All other lines were relatively resistant to TRAIL-induced apoptosis. Activating TRAIL receptors DR4 and DR5 were expressed in all normal and malignant breast cell lines. The inhibitory receptor TRID was highly expressed in one of four normal and two of seven malignant breast cell lines. DR4, DR5, or TRID expression did not correlate with sensitivity to TRAIL-induced apoptosis. Incubation of cell lines with doxorubicin or 5-fluorouracil significantly augmented TRAIL-induced apoptosis in most breast cell lines. By fractional inhibition analysis, the toxicity of the combination of TRAIL and doxorubicin or 5-fluorouracil was synergistic compared with either agent alone. In contrast, melphalan and paclitaxel augmented TRAIL-induced apoptosis in few cell lines, and methotrexate did not augment it in any cell line. Augmentation of TRAIL-induced apoptosis by doxorubicin or 5-fluorouracil was mediated through caspase activation. This was evidenced by the fact that chemotherapy agents that synergized with TRAIL (e.g., doxorubicin) themselves caused cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), and their toxicity was blocked by the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2 (ZVAD-fmk). The combination of TRAIL and doxorubicin caused significantly greater caspase-3 and PARP cleavage, and the combined toxicity also was inhibited by ZVAD-fmk. In contrast, chemotherapy agents that did not augment TRAIL-induced apoptosis (e.g., methotrexate) caused minimal caspase-3 and PARP cleavage by themselves, and their toxicity was not inhibited by ZVAD-fmk. These drugs also did not increase caspase-3 or PARP cleavage when combined with TRAIL. In summary, few breast cell lines are sensitive to TRAIL-induced apoptosis, and no difference in sensitivity is found between normal and malignant cell lines. Treatment with chemotherapy provides an approach to sensitize breast cancer cells to TRAIL-induced apoptosis.
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PMID:Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. 997 25

Glutathione (GSH) depletion caused by l-buthionine-(S,R)-sulfoximine (BSO) induced apoptosis that was recognized by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick endo-labeling (TUNEL), nuclear DNA staining with fluorescence dye, and internucleosomal DNA fragmentation in C6 rat glioma cells. The BSO-induced cell death was associated with caspase-3 activation. Lipid peroxidation and protein kinase C (PK-C) activation were observed during the apoptosis of C6 cells, and these events were inhibited by antioxidants and iron chelators without affecting BSO-induced GSH depletion. Furthermore, approximately 2 Mbp giant DNA fragments were observed in the BSO-treated cells. The giant DNA fragmentation were followed by approximately 30-700 kbp and then less than 100 kbp, including internucleosomal DNA fragmentations. Such serial DNA degradation was prevented by the antioxidants, the iron chelators, and the PK-C inhibitors. These results suggest that during apoptosis induced by GSH-depletion caused by BSO, reactive oxygen species endogenously produced cause lipid peroxidation and that the lipid peroxidation induced PK-C activation, processes which are thought to be involved in the giant DNA, high-molecular-weight DNA, and the internucleosomal DNA fragmentations.
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PMID:Glutathione depletion induces giant DNA and high-molecular-weight DNA fragmentation associated with apoptosis through lipid peroxidation and protein kinase C activation in C6 glioma cells. 1004 97

Glutathione-doxorubicin (GSH-DXR) effectively induced apoptosis in rat hepatoma cells (AH66) at a lower concentration than DXR. After 24 h of drug treatment, DNA fragmentation of the cells was observed at the concentration of 1.0 microM DXR or 0.01 microM GSH-DXR. Increase in caspase-3 activity and DNA fragmentation were observed within 12 h and 15 h after treatment with either drug. Intracellular caspase-3 activity was increased in a dose-dependent manner after treatment with DXR or GSH-DXR, and caspase-3 activity correlated well with the ability to induce DNA fragmentation. When the cells were treated with either DXR or GSH-DXR for only 6 h, apoptotic DNA degradation and caspase-3 activation occurred 24 h after treatment. DNA fragmentation caused by these drugs was prevented completely by simultaneous treatment with the caspase-3 inhibitor, acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO), at 10 microM. By contrast, DNA fragmentation was not prevented by the caspase-1 inhibitor, acetyl-Tyr-Val-Ala-Asp-aldehyde (YVAD-CHO), at the same concentration as DEVD-CHO, and caspase-1 was not activated at all by the treatment of AH66 cells with both DXR and GSH-DXR. These results demonstrate that DXR and GSH-DXR induce apoptotic DNA fragmentation via caspase-3 activation, but not via caspase-1 activation, and that GSH-DXR enhances the activation of caspase-3 approximately 100-fold more than DXR. Moreover, the findings suggested that an upstream apoptotic signal that can activate caspase-3 is induced within 6 h by treating AH66 cells with the drug.
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PMID:Caspase-3 activation during apoptosis caused by glutathione-doxorubicin conjugate. 1036 Jun 48

Resolution of neutrophil mediated inflammation is achieved, in part, through induction of neutrophil apoptosis. This constitutively expressed programme can be delayed by inflammatory mediators and induced by ligation of the Fas receptor. However, functional activation of the neutrophil results in resistance to Fas signalled death. We evaluated the effects of Fas antibody engagement on caspase activation and mitochondrial permeability, and the impact of co-stimulation by lipopolysaccharide (LPS) or granulocyte macrophage-colony stimulating factor (GM-CSF) on these events. Fas engagement by an agonistic anti-Fas antibody resulted in enhanced caspase 3 and 8 activity and increased mitochondrial permeability. Studies with pharmacological inhibitors of caspase activity showed that activation of caspase 8 occurred before, and activation of caspase 3 occurred after mitochondrial disruption. The mitochondrial stabilising agent bongkrekic acid also inhibited caspase activation and apoptosis. LPS, GM-CSF and increased glutathione stabilised the mitochondria and inhibited caspase 3. Caspase 8 activity was also inhibited by co-stimulation through a mechanism independent of mitochondrial stabilisation. Glutathione directly inhibited caspase 3 and 8 activity. We conclude inhibition of Fas antibody induced apoptosis by inflammatory proteins is associated with augmented mitochondrial stability and reduced caspase 3 activity that may be glutathione mediated.
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PMID:Regulation of Fas antibody induced neutrophil apoptosis is both caspase and mitochondrial dependent. 1040 77

Low concentrations of As(2)O(3) (</=1 micromol/L) induce long-lasting remission in patients with acute promyelocytic leukemia (APL) without significant myelosuppressive side effects. Several groups, including ours, have shown that 0.5 to 1 micromol/L As(2)O(3) induces apoptosis in APL-derived NB4 cells, whereas other leukemic cells are resistant to As(2)O(3) or undergo apoptosis only in response to greater than 2 micromol/L As(2)O(3). In this report, we show that the ability of As(2)O(3) to induce apoptosis in leukemic cells is dependent on the activity of the enzymes that regulate cellular H(2)O(2) content. Thus, NB4 cells have relatively low levels of glutathione peroxidase (GPx) and catalase and have a constitutively higher H(2)O(2) content than U937 monocytic leukemia cells. Glutathione-S-transferase pi (GSTpi), which is important for cellular efflux of As(2)O(3), is also low in NB4 cells. Moreover, As(2)O(3) further inhibits GPX activity and increases cellular H(2)O(2) content in NB4 but not in U937 cells. Selenite pretreatment of NB4 cells increases the activity of GPX, lowers cellular H(2)O(2) levels, and renders NB4 cells resistant to 1 micromol/L As(2)O(3). In contrast, concentrations of As(2)O(3) that alone are not capable of inducing apoptosis in NB4 cells induce apoptosis in the presence of the GPx inhibitor mercaptosuccinic acid. Similar effects are observed by modulating the activity of catalase with its inhibitor, aminotriazol. More important from a therapeutic point of view, U937 and HL-60 cells, which require high concentrations of As(2)O(3) to undergo apoptosis, become sensitive to low, clinically acceptable concentrations of As(2)O(3) when cotreated with these GPx and catalase inhibitors. The induction of apoptosis by As(2)O(3) involves an early decrease in cellular mitochondrial membrane potential and increase in H(2)O(2) content, followed by cytochrome c release, caspase 3 activation, DNA fragmentation, and the classic morphologic changes of apoptosis.
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PMID:Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway. 1047 40

In this study, both NIH3T3 and Bcl-2 transfected NIH3T3 cells were examined for their propensity to undergo nitroso compound-induced apoptosis. Bcl-2-expressing NIH3T3 prevented N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)- and S-nitrosoglutathione (GSNO)-induced apoptosis as compared with the control NIH3T3 cells. Flow cytometry revealed that NIH3T3 cells treated with MNNG undergo apoptotic death, which occurred after G2-M arrest in the second cycle of cell proliferation. The mechanism of MNNG-induced NIH3T3 cells apoptosis was observed throughout the activation of caspase-3 protease, PARP degradation and cytochrome c release; it was independent of p53 activation. Glutathione-S-transferanse pi (GST pi) is activated through the transcription activation of antioxidant response element (ARE) during MNNG- and GSNO-induced cell apoptosis. Moreover, overexpression of Bcl-2 in NIH3T3 cells can prevent these features of cell death. Furthermore, both MNNG- and GSNO-induced apoptosis of NIH3T3 cells were accompanied with a decrease in the level of glutathione (GSH); whereas Bcl-2 overexpression led to an increase in total cellular glutathione. MNNG was metabolized rapidly to nitric oxide that reacted with glutathione under the catalysis of GSH transferase in NIH3T3 cell to form GSNO. In short, the production of GSNO in cells was found capable of apoptosis initiation while the overexpression of Bcl-2 can prevent MNNG-mediated cell apoptosis through the elevation of glutathione levels.
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PMID:Suppression of N-methyl-N'-nitro-N-nitrosoguanidine- and S-nitrosoglutathione-induced apoptosis by Bcl-2 through inhibiting glutathione-S-transferase pi in NIH3T3 cells. 1059 28

Glutathione depletion either decreased or increased death-receptor-mediated apoptosis in previous studies. Comparison of the durations of glutathione depletion before death-receptor stimulation in these studies might suggest a different effect of prolonged versus acute thiol depletion. We compared the effects of the prolonged glutathione depletion caused by a sulfur amino acid-deficient (SAA(-)) diet and the acute depletion caused by a single dose of phorone on hepatic apoptosis triggered by the administration of an agonistic anti-Fas antibody. The chronic SAA(-) diet did not affect hepatic Fas or Bcl-XL, but increased p53 and Bax, and exacerbated Fas-mediated mitochondrial membrane depolarization, electron-microscopy-proven outer mitochondrial membrane rupture, cytochrome c translocation to the cytosol, and caspase 3 activation. These effects were prevented by cyclosporin A, an inhibitor of mitochondrial permeability transition. The SAA(-) diet increased internucleosomal DNA fragmentation, the percentage of apoptotic hepatocytes, serum alanine transaminase (ALT) activity, and mortality after Fas stimulation. Despite a similar decrease in hepatic glutathione, administration of a single dose of phorone 1 hour before the anti-Fas antibody did not change p53 or Bax, and did not enhance Fas-induced mitochondrial permeability transition and toxicity. However, 4 repeated doses of phorone (causing more prolonged glutathione depletion) increased Bax and Fas-mediated toxicity. In conclusion, a chronic SAA(-) diet, but not acute phorone administration, increases p53 and Bax, and enhances Fas-induced mitochondrial permeability transition and apoptosis. Thiol depletion could cause oxidative stress that requires several hours to increase p53; the latter induces Bax, which translocates to mitochondria after Fas stimulation.
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PMID:Prolonged, but not acute, glutathione depletion promotes Fas-mediated mitochondrial permeability transition and apoptosis in mice. 1134 47

Proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada; organized and co-chaired by Patricia E. Molina and Manuela Neuman. The presentations were (1) Mechanisms of alcohol-induced cell injury by Craig McClain; (2) Cytokines in alcoholic steatohepatitis and non-alcoholic steatohepatitis by Manuela Neuman; (3) Combination of alcohol and hepatitis C virus and liver injury by Dominique Valla; (4) Chronic ethanol exposure potentiates lipopolysaccharide liver injury, despite inhibiting Jun N-Terminal kinase and caspase 3 activation by Anna Mae Diehl; (5) Glutathione homeostasis in alcoholism: Role in alveolar epithelial barrier and lung injury by David M. Guidot; (6) Metabolic and inflammatory contribution of alcohol to trauma-induced tissue injury by Patricia E. Molina; (7) Growth factor and protein synthesis dysregulation: Role in alcoholic myopathy by Charles H. Lang.
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PMID:Molecular pathology and clinical aspects of alcohol-induced tissue injury. 1182 62

Oxysterols have been shown in a number of cell lines to induce apoptosis by a mechanism as yet unclear. The induction of apoptosis by certain agents has been associated with the generation of oxidative stress and the depletion of the endogenous antioxidant, glutathione, which may result in cytochrome c release and caspase activation. The aim of the present study was to determine whether 7 beta-hydroxycholesterol (7 beta-OH) alters glutathione levels or the activities of catalase, superoxide dismutase (SOD) or caspase-3 in association with cell death in either the U937 or the HepG2 cell lines. 7 beta-OH, which induced significant apoptosis at 12 h in the U937 cell line, was shown to cause a significant decrease in glutathione levels and an increase in the activity of SOD at this time point. An increase in caspase-3 activity was also observed in the U937 cell line following a 24-h incubation with 7 beta-OH. Glutathione concentration, SOD activity and caspase-3 activity were unchanged in the HepG2 cell line, which underwent necrosis following incubation with 7 beta-OH. The activity of the enzyme catalase remained unchanged in both cell lines. These results provide evidence that the generation of an oxidative stress may be a significant event occurring during 7 beta-OH-induced apoptosis.
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PMID:Characteristics of 7 beta-hydroxycholesterol-induced cell death in a human monocytic blood cell line, U937, and a human hepatoma cell line, HepG2. 1202 May 97

Mesothelioma is a fatal tumor resistant to all treatment modalities for reasons that are still unresolved. Glutathione (GSH)-associated pathways are induced by oxidants and cytotoxic drugs, and they are also involved in the progression and resistance of some tumor cells in vitro. The rate-limiting enzyme in GSH biosynthesis is gamma-glutamylcysteine synthetase (gamma GCS). However, the expression of this enzyme has not been systematically investigated in malignant tumors, and there are no studies of gamma GCS in biopsy specimens of malignant mesothelioma. We investigated the immunohistochemical distribution and expression of both subunits of gamma GCS in healthy pleural mesothelium, pleural mesothelioma tumor biopsy samples (34 cases), and mesothelioma cells in culture (7 cell lines). Nonmalignant mesothelium showed no immunoreactivity for either subunit in any of the cases. The heavy (catalytic) subunit of gamma GCS was highly immunostained in 29 and weakly positive in 5 cases. High-moderate and weak immunoreactivity of the light (regulatory) subunit of gamma GCS was found in 15 and 7 tumors, respectively, whereas 12 cases showed no reactivity. There was no correlation with either catalytic or regulatory subunit expression and patient survival. There was, however, a significant correlation between the heavy chain and multidrug resistance protein (MRP) 2 (P =.048), whereas no correlation was observed between the light chain and MRP1 or MRP2. Treatment of cultured mesothelioma cells with buthionine sulfoximine (BSO), to inhibit gamma GCS, significantly potentiated cisplatin-induced cytotoxicity mainly by nonapoptotic mechanism when assessed by counting the living cells, TUNEL (terminal deoxytransferase-mediated dUTP nick-end labeling) assay, and caspase-3 cleavage. In conclusion, gamma GCS is highly positive in most cases of malignant mesothelioma and may play an important role in the primary drug resistance of this tumor in vivo.
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PMID:Overexpression of gamma-glutamylcysteine synthetase in human malignant mesothelioma. 1219 27

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