Nitric Oxide Reversibly Inhibits Seven Members of the Caspase Family via S-Nitrosylation

Lǐ, Jiànróng; Billiar, Timothy R.; Talanian, Robert V.; Kim, Young Beom

doi:10.1006/bbrc.1997.7672

Cited by 496 publications

(327 citation statements)

References 43 publications

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“…NO has been shown to inhibit endothelial cell apoptosis 23 and many groups have shown inhibitory effects of NO on caspase activity. [20][21][22][23][24][25] Diminished eNOS-catalyzed production of NO or its bioavailability leads to endothelial apoptosis, and it has been speculated that this is associated with enhanced susceptibility to endothelial dysfunction and atherosclerosis. [26][27][28] As NO inhibits apoptosis in endothelial cells, it is intriguing to speculate that caspase-mediated loss of eNOS-derived NO further activates the caspase cascade, thereby promoting the apoptotic process by removing an impediment to cell death.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 NO can have either pro-or antiapoptotic effects in different types of cells, dependent on its concentration and the overall oxidative status of the cell, among other factors. [18][19][20] Antiapoptotic effects of NO have been attributed to its ability to inhibit the caspase cascade via reversible S-nitrosylation of key cysteine residues in various caspases. [20][21][22][23][24] Thus, eNOS-synthesized NO inhibited caspase-mediated apoptosis in endothelial cells; 23 it has been speculated that diminished production or availability of NO and enhanced apoptosis is related to susceptibility to atherosclerosis or age-related endothelial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

“…[18][19][20] Antiapoptotic effects of NO have been attributed to its ability to inhibit the caspase cascade via reversible S-nitrosylation of key cysteine residues in various caspases. [20][21][22][23][24] Thus, eNOS-synthesized NO inhibited caspase-mediated apoptosis in endothelial cells; 23 it has been speculated that diminished production or availability of NO and enhanced apoptosis is related to susceptibility to atherosclerosis or age-related endothelial dysfunction. [25][26][27][28] In view of a role for eNOS in endothelial cell apoptosis, the effect of staurosporine-induced apoptosis on levels of eNOS protein and activity was studied in COS-7 cells, overexpressing eNOS, and in bovine aortic endothelial cells (BAEC).…”

Section: Introductionmentioning

confidence: 99%

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Effect of staurosporine-induced apoptosis on endothelial nitric oxide synthase in transfected COS-7 cells and primary endothelial cells

2005

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Nitric oxide (NO) may block apoptosis by inhibiting caspases via S-nitrosylation of cysteines. Here, we investigated whether effector caspases might cleave and thereby inhibit endothelial nitric oxide synthase (eNOS). Exposure of eNOS-transfected COS-7 cells and bovine aortic endothelial cells to staurosporine resulted in significant loss of 135-kDa eNOS protein and activity, and appearance of a 60-kDa eNOS fragment; effects were inhibited by the general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp[OMe]-fluoromethyl ketone (zVAD-fmk). In eNOS-transfected COS-7 cells, staurosporine-induced activation of caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage coincided with increased eNOS degradation and decreased activity. Loss of eNOS activity was greater than the degree of proteolysis. Incubation of immunoprecipitated eNOS with caspase-3, caspase-6 or caspase-7 resulted in eNOS cleavage. Staurosporine, a general protein kinase inhibitor, also reduced phosphorylation and decreased calmodulin binding, an effect that may explain the reduction in activity. eNOS, therefore, is both an inhibitor of apoptosis and a target of apoptosis-associated proteolysis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of staurosporine-induced apoptosis on endothelial nitric oxide synthase in transfected COS-7 cells and primary endothelial cells

2005

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“…Other reports demonstrated that inhibition of caspase activity might occur by S-nitrosylation of cysteine residues in the active site of the caspases (Li et al, 1997;Maejima et al, 2005). In order to elucidate the mechanism of IL-1b-mediated caspase inhibition, we first analysed iNOS expression and NO secretion in PT45-P1 and PT45-P1res cells.…”

Section: Resultsmentioning

confidence: 99%

Acquired chemoresistance in pancreatic carcinoma cells: induced secretion of IL-1β and NO lead to inactivation of caspases

et al. 2006

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Pancreatic cancer exhibits profound chemoresistance resulting either from pre-existing (intrinsic) mechanisms, or from anticancer drug treatment itself (acquired chemoresistance). To identify molecular alterations leading to acquired chemoresistance, the chemosensitive pancreatic carcinoma cell line PT45-P1 was exposed to low-dose treatment with etoposide for 6 weeks. Afterwards, these cells (PT45-P1res) were much more resistant to high-dose treatment with anticancer drugs than parental cells. Among several differentially expressed genes in PT45-P1res cells, IL-1b was most significantly upregulated, a finding in line with our previous observation that IL-1b accounts for intrinsic chemoresistance of pancreatic carcinoma cells. Elevated IL-1b expression in PT45-P1res cells was confirmed by real-time PCR and ELISA, and treatment with the IL-1 receptor antagonist restored drug-induced apoptosis. The increased IL-1b secretion was accompanied by an elevated formation of nitric oxide (NO) and a NO-dependent inhibition of the etoposide-induced caspase-3/-7/-8/-9 activity. Caspase activation was restored either by the iNOS inhibitor 1400W, the reducing agent dithiothreitol or the IL-1 receptor antagonist, resulting in greater sensitivity towards anticancer drug treatment. Conversely, IL-1b or the NO-donor SNAP decreased caspase activation and apoptosis in etoposide-treated PT45-P1 cells. These data confirm IL-1b and NO as determinants of chemoresistance in pancreatic cancer, and indicate that the intrinsic and acquired chemoresistance rely to some extent on common molecular targets beneficial for improved therapeutical strategies.

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“…It has been shown to inhibit the activity of Caspase 3, thus preventing apoptosis. 27 However, it has been shown to mediate down -regulation of Bcl2, an anti-apoptotic factor, in melanoma cells. 28 In fact, the final outcome seems to depend on the NO level and the pathway used in the target cell.…”

Section: Discussionmentioning

confidence: 99%

Regression of primary hepatocarcinoma in cancer-prone transgenic mice by local interferon-γ delivery is associated with macrophages recruitment and nitric oxide production

et al. 2001

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The clinical potential of tumor therapies must be evaluated using animal models closely resembling human cancers. We investigated the impact of locally delivered interferon -(IFN-) on primary hepatocarcinoma spontaneously developed by T -SV40 transgenic mice. A single intratumor injection of adenovirus IFN -was sufficient enough to induce in vivo production of biologically active IFN -, as assessed by STAT1 activation. IFN -secretion led to the regression of primary tumor, principally by apoptosis of tumor hepatocytes. The lack of T -cells infiltrates in the liver upon treatment excluded a role of a specific immune response. In contrast, indirect pathways may include tumoricidal function of macrophages. Indeed, they were massively recruited in the entire liver under IFN -treatment; transmigration through hepatic blood vessels could be observed and co -localization with damaged hepatocytes was obvious. This correlated with nonparenchymal liver cell iNOS expression and high level of NO in hepatic extracts. Moreover, in vitro experiments showed that NO releasing agents induced cell death of freshly isolated tumor hepatocytes, suggesting that NO could be one of the major effector molecules. Altogether, these observations defined an important role of IFN -in controlling tumor development in a model of primary hepatocarcinoma.

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Nitric Oxide Reversibly Inhibits Seven Members of the Caspase Family via S-Nitrosylation

Cited by 496 publications

References 43 publications

Effect of staurosporine-induced apoptosis on endothelial nitric oxide synthase in transfected COS-7 cells and primary endothelial cells

Effect of staurosporine-induced apoptosis on endothelial nitric oxide synthase in transfected COS-7 cells and primary endothelial cells

Acquired chemoresistance in pancreatic carcinoma cells: induced secretion of IL-1β and NO lead to inactivation of caspases

Regression of primary hepatocarcinoma in cancer-prone transgenic mice by local interferon-γ delivery is associated with macrophages recruitment and nitric oxide production

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