Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that nitric oxide (NO) stimulates apoptosis in different human neoplastic lymphoid cell lines through activation of caspases not only via CD95/CD95L interaction, but also independently of such death receptors. Here we investigated mitochondria-dependent mechanisms of NO-induced apoptosis in Jurkat leukemic cells. NO donor glycerol trinitrate (at the concentration, which induces apoptotic cell death) caused (1) a significant decrease in the concentration of cardiolipin, a major mitochondrial lipid; (2) a downregulation in respiratory chain complex activities; (3) a release of the mitochondrial protein cytochrome c into the cytosol; and (4) an activation of caspase-9 and caspase-3. These changes were accompanied by an increase in the number of cells with low mitochondrial transmembrane potential and with a high level of reactive oxygen species production. Higher resistance of the CD95-resistant Jurkat subclone (APO-R) cells to NO-mediated apoptosis correlated with the absence of cytochrome c release and with less alterations in other mitochondrial parameters. An inhibitor of lipid peroxidation, trolox, significantly suppressed NO-mediated apoptosis in APO-S Jurkat cells, whereas bongkrekic acid (BA), which blocks mitochondrial permeability transition, provided only a moderate antiapoptotic effect. Transfection of Jurkat cells with bcl-2 led to a complete block of apoptosis due to the prevention of changes in mitochondrial functions. We suggest that the mitochondrial damage (in particular, cardiolipin degradation and cytochrome c release) induced by NO in human leukemia cells plays a crucial role in the subsequent activation of caspase and apoptosis.
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PMID:Nitric-oxide-induced apoptosis in human leukemic lines requires mitochondrial lipid degradation and cytochrome C release. 1009 Sep 45

We have attempted to elucidate the precise mechanism of nitric oxide (NO)-induced apoptotic neuronal cell death. Enzymatic cleavages of DEVD-AFC, VDVAD-AFC, and LEHD-AFC (specific substrates for caspase-3-like protease (caspase-3 and -7), caspase-2, and caspase-9, respectively) were observed by treatment with NO. Western blot analysis showed that pro-forms of caspase-2, -3, -6, and -7 are decreased during apoptosis. Interestingly, Ac-DEVD-CHO, a caspase-3-like protease inhibitor, blocked not only the decreases in caspase-2 and -7, but also the formation of p17 from p20 in caspase-3 induced by NO, suggesting that caspase-3 exists upstream of caspase-2 and -7. Bongkrekic acid, a potent inhibitor of mitochondrial permeability transition, specifically blocked both the loss of mitochondrial membrane potential and subsequent DNA fragmentation in response to NO. Thus, NO results in neuronal apoptosis through the sequential loss of mitochondrial membrane potential, caspase activation, and degradation of inhibitor of caspase-activated DNase (CAD) (CAD activation).
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PMID:Mechanism of nitric oxide-induced apoptosis in human neuroblastoma SH-SY5Y cells. 1107 88

High amounts of nitric oxide (NO) produced by activated macrophages or NO donors are required to induce cytotoxicity and apoptosis in pathogens and tumor cells. High concentrations of NO may lead to nonspecific toxicity thereby limiting the use of NO donors in the treatment of cancer. In this study, we tested the possibility of potentiating the apoptotic action of NO in a human breast cancer cell line, MDA-MB-468, by combining it with a farnesyltransferase inhibitor (FTI), which has been shown to induce apoptosis in some other cancer cell lines with minimal toxicity to normal cells. DETA-NONOate, a long acting NO donor which has a half-life of 20 h at 37 degrees C, was used in this study. DETA-NONOate (1 mM), which releases NO in the range produced by activated macrophages, induced apoptosis after 36 h in MDA-MB-468 cells via cytochrome c release and caspase-9 and -3 activation. FTI (25 microM) potentiated the action of lower concentrations of DETA-NONOate (25-100 microM) by inducing apoptosis in these cells within 24 h by increasing cytochrome c release and caspase-9 and -3 activation. This effect was observed preferentially in the cancer cell lines studied with no apoptosis induction in normal breast epithelial cells. This novel combination of FTI and NO may emerge as a promising approach for the treatment of breast cancer.
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PMID:Potentiation of nitric oxide-induced apoptosis of MDA-MB-468 cells by farnesyltransferase inhibitor: implications in breast cancer. 1140 40

The present study examined the role of nitric oxide in cocaine-induced apoptosis in bovine coronary artery endothelial cells (BCAECs). Cocaine produced a time-dependent decrease in cell viability and an increase in apoptosis in BCAECs, which were blocked by the nitric oxide donors DETA-NONOate (DETA-NO) and S-nitroso-N-acetyl-penicillamine. In accordance, cocaine decreased nitric oxide production in BCAECs at each time point of the study. Cocaine significantly increased caspase-3 activity that was blocked by the inhibitors of cytochrome c release (cyclosporin A), caspase-3 (Ac-DEVD-CHO), and caspase-9 (Z-LEHD-FMK), respectively. In addition, cocaine activated caspase-9, which was blocked by cyclosporin A and Z-LEHD-FMK. Ac-DEVD-CHO only partially blocked cocaine-induced caspase-9 activity. DETA-NO (20 microM) blocked cocaine-mediated activation of both caspase-9 and caspase-3. Cocaine decreased Bcl-2 protein levels, which was partially blocked by Ac-DEVD-CHO and Z-LEHD-FMK, but not by DETA-NO. Furthermore, cocaine induced a translocation of Bax from the cytosol to the mitochondria in BCAECs, and increased Bax levels in mitochondria by 2.2-fold. In accordance, cytosolic Bax levels decreased about 42%. Neither Ac-DEVD-CHO nor DETA-NO affected cocaine-induced translocation of Bax. We conclude that cocaine-induced Bcl-2 protein down-regulation and Bax translocation to the mitochondria are upstream signals of caspase-9 activation that precedes caspase-3. Cocaine-induced attenuation of nitric oxide plays a key role in the activation of the caspase cascade in BCAECs.
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PMID:Cocaine-mediated apoptosis in bovine coronary artery endothelial cells: role of nitric oxide. 1140 40

Axotomised dorsal root ganglia (DRG) neurons show an increased expression of neuronal nitric oxide synthase (nNOS) compared with neurons from the intact ganglia. Increased nNOS expression resulted in synthesis of nitric oxide (NO) and the subsequent activation of cGMP in satellite glia cells surrounding the DRG neuron soma. In dissociated DRG we have demonstrated that the increase in nNOS expression is regulated by nerve growth factor and that the subsequent inhibition of NO production or cGMP synthesis precipitates apoptosis of neurons expressing nNOS and some non-nNOS neurons. Hence, NO or the NO-cGMP cascade appears to have a neuroprotective action in trophic factor-deprived DRG neurons. In the present study, using immunocytochemistry, we have investigated some of the factors associated with apoptosis that are activated when nNOS activity is blocked with NOS inhibitor in DRG neurons in vitro. Marked elevation of bax was observed within a few hours of NOS inhibition in nNOS containing neurons, whereas pretreatment of cultures with l-arginine completely abolished this effect in almost all nNOS neurons and 8-bromo-cGMP in some neurons. The apoptosis precipitated by NOS inhibition was also partially prevented by a number of caspase inhibitors; of those a caspase-9 blocker was the most effective. These observations further support the neuroprotective role of NO/NO-cGMP in stressed DRG neurons in an autocrine fashion that involves the suppression of bax, caspase-3 and -9 activation.
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PMID:Bax and caspases are inhibited by endogenous nitric oxide in dorsal root ganglion neurons in vitro. 1170 52

Nitric oxide (NO) can induce apoptosis in a variety of cell types. A non-toxic concentration of nitric oxide under normal oxygen conditions triggered cell death under hypoxic conditions (1.5% O(2)) in fibroblasts. Nitric oxide administered during hypoxia induced the release of cytochrome c, caspase-9 activation, and the loss of mitochondrial membrane potential followed by DNA fragmentation and lactate dehydrogenase release (markers of cell death). Bcl-X(L) protected cells from nitric oxide-induced apoptosis during hypoxia by preventing the release of cytochrome c, caspase-9 activation, and by maintaining a mitochondrial membrane potential. Murine embryonic fibroblasts from bax(-/-) bak(-/-) mice exposed to nitric oxide during hypoxia did not die, indicating that pro-apoptotic Bcl-2 family members are required for NO-induced apoptosis during hypoxia. The nitric oxide-induced cell death during hypoxia was independent of cGMP and peroxynitrite. Cells devoid of mitochondrial DNA (rho secondary-cells) lack a functional electron transport chain and were resistant to nitric oxide-induced cell death during hypoxia, suggesting that a functional electron transport chain is required for nitric oxide-induced apoptosis during hypoxia.
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PMID:Hypoxia sensitizes cells to nitric oxide-induced apoptosis. 1186 45

Nitric oxide (NO) is an environmental pollutant found in smog and cigarette smoke. Recently, NO has been discovered to act as a molecular messenger, mediating various physiological functions. However, when an excess of NO is present, cytotoxic and mutagenic effects can also be induced. The reaction of NO with superoxide results in the formation of peroxynitrite (ONOO(-)), which decomposes into the hydroxyl radical and nitrogen dioxide. Both of them are potent oxidant species that may initiate and propagate lipid peroxidation. In the present study, we examined the effects of NO and ONOO(-) on the induction of lipid peroxidation and cell death mechanisms in rats and in A549 pulmonary epithelial cells. The results showed that ONOO(-) is able to induce lipid peroxidation in pulmonary epithelial cells in a dose-dependent manner. 8-Epi-prostaglandin F(2)(alpha) can serve as a good biomarker of lipid peroxidation both in vitro and in vivo. Postmitotic apoptosis was found in A549 cells exposed to NO, whereas ONOO(-) induced cell death more characteristic of necrosis than apoptosis. Apoptosis that occurred in cells may be related to the dysfunction of mitochondria, the release of cytochrome c into cytosol, and the activation of caspase-9. The relationship between caspase activation and the cleavage of other death substrates during postmitotic apoptosis in A549 cells needs further investigation.
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PMID:Lipid peroxidation and cell death mechanisms in pulmonary epithelial cells induced by peroxynitrite and nitric oxide. 1218 18

Photodynamic therapy (PDT) of cancer is a very promising technique based on the formation of singlet oxygen induced by a sensitizer after irradiation with visible light. The stimulation of tumor growth by nitric oxide (NO) was reported recently, and NO was shown to have a protective effect against PDT-induced tumor death. We investigated a putative direct effect of NO on tumor cell death induced by PDT, using the human lymphoblastoid CCRF-CEM cells and bisulfonated aluminum phthalocyanine (AlPcS2) as a sensitizer. Cells were incubated with AlPcS2 in the presence or absence of NO donors ((Z)-1-[(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate, hydroxylamine and S-nitroso-N-acetylpenicillamine) or L-arginine. Under these conditions, in the absence of NO donors or L-arginine the cells died rapidly by apoptosis upon photosensitization. In the presence of NO donors or L-arginine, apoptotic cell death after photosensitization was significantly decreased. Modulation of cell death by NO was not due to S-nitrosylation of caspases and occurred at the level or upstream of caspase-9 processing. The protective effect of NO was reversed by incubating the cells with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of guanylyl cyclase, or with KT5823, an inhibitor of protein kinase G (PKG). Incubation with 8-bromo-cyclic guanosine monophosphate, a membrane permeable cyclic guanosine monophosphate analog, also decreased cell death induced by PDT. Although the protective effect of NO against apoptotic cell death in several models has been attributed to an increase in the expression of heme oxygenase-1, heat shock protein 70 or Bcl-2, this was not the case under our experimental conditions. These results show that NO decreases the extent of apoptotic cell death after PDT treatment through a PKG-dependent mechanism, upstream or at the level of caspase activation.
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PMID:Nitric oxide modulates tumor cell death induced by photodynamic therapy through a cGMP-dependent mechanism. 1240 51

In the absence of survival factors, blood monocytes undergo spontaneous apoptosis, which involves the activation of caspase-3. Although nitric oxide can block caspase-3 activation and promote cell survival, it can also induce apoptosis. We hypothesized that nitrosothiols that promote protein S-nitrosylation would reduce caspase-3 activation and cell survival, whereas nitric oxide donors (such as 1-propamine 3-(2-hydroxy-2-nitroso-1-propylhydrazine (PAPA) NONOate and diethylamine (DEA) NONOate) that do not target thiol residues would not. Using human monocytes as a model, we observed that nitrosothiol donors S-nitrosoglutathione and S-nitroso-N-acetylpenicillamine suppressed caspase-9 and caspase-3 activity and DNA fragmentation. In contrast, PAPA or DEA NONOate did not promote monocyte survival events and appeared to inhibit monocyte survival induced by macrophage colony-stimulating factor. The caspase-3-selective inhibitor DEVD-fluoromethyl ketone reversed DNA fragmentation events, and the caspase-9 inhibitor LEHD-fluoromethyl ketone reversed caspase-3 activity in monocytes treated with PAPA or DEA NONOate in the presence of macrophage colony-stimulating factor. These results were not caused by differences in glutathione levels or the kinetics of nitric oxide release. Moreover, S-nitrosoglutathione and S-nitroso-N-acetylpenicillamine directly blocked the activity of recombinant caspase-3, which was reversed by the reducing agent dithiothreitol, whereas PAPA or DEA NONOate did not block the enzymatic activity of caspase-3. These data support the hypothesis that nitrosylation of protein thiol residues by nitric oxide is critical for promoting the survival of human monocytes.
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PMID:Presentation of nitric oxide regulates monocyte survival through effects on caspase-9 and caspase-3 activation. 1256 44

Caspases are critical for the initiation and execution of apoptosis. Nitric oxide (NO) or derived species can prevent programmed cell death in several cell types, reportedly through S-nitrosation and inactivation of active caspases. Although we find that S-nitrosation of caspases can occur in vitro, our study questions whether this post-translational modification is solely responsible for NO-mediated inhibition of apoptosis. Indeed, using Jurkat cells as a model system, we demonstrate that NO donors block Fas- and etoposide-induced caspase activation and apoptosis (downstream of mitochondrial membrane depolarization) and cytochrome c release. However, caspase activity was not restored by the strong reducing agent dithiothreitol, as predicted for S-nitrosation reactions, thereby excluding active-site-thiol modification of caspases as the only anti-apoptotic mechanism of NO donors in cells. Rather, we observed that processing of procaspases-9, -3 and -8 was decreased due to ineffective formation of the Apaf-1/caspase-9 apoptosome. Gel-filtration and in vitro binding assays indicated that NO donors inhibit correct assembly of Apaf-1 into an active approx. 700 kDa apoptosome complex, and markedly attenuate caspase-recruitment domain (CARD)-CARD interactions between Apaf-1 and procaspase-9. Therefore we suggest that NO or a metabolite acts directly at the level of the apoptosome and inhibits the sequential activation of caspases-9, -3 and -8, which are required for both stress- and receptor-induced death in cells that use the mitochondrial subroute of cell demise.
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PMID:Nitric oxide donors inhibit formation of the Apaf-1/caspase-9 apoptosome and activation of caspases. 1260 97


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