Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.60 (caspase-7)
 920 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Fas/Fas ligand (FasL) pathway is widely involved in apoptotic cell death in lymphoid and nonlymphoid cells. It has recently been postulated that many chemotherapeutic agents also induce cell death by activating the Fas/FasL pathway. In the present study we compared apoptotic pathways induced by anti-Fas or chemotherapeutic agents in the Jurkat human T-cell leukemia line. Immunoblotting showed that treatment of wild-type Jurkat cells with anti-Fas or the topoisomerase II-directed agent etoposide resulted in proteolytic cleavage of precursors for the cysteine-dependent aspartate-directed proteases caspase-3 and caspase-7 and degradation of the caspase substrates poly(ADP-ribose) polymerase (PARP) and lamin B1. Likewise, affinity labeling with N-(N(alpha)-benzyloxycarbonylglutamyl-N(epsilon)-biotinyllysyl+ ++)aspartic acid [(2,6-dimethyl-benzoyl)oxy]methyl ketone [Z-EK(bio)D-amok] labeled the same five active caspase species after each treatment, suggesting that the same downstream apoptotic pathways have been activated by anti-Fas and etoposide. Treatment with ZB4, an antibody that inhibits Fas-mediated cell death, failed to block etoposide-induced apoptosis, raising the possibility that etoposide does not initiate apoptosis through Fas/FasL interactions. To further explore the relationship between Fas- and chemotherapy-induced apoptosis, Fas-resistant Jurkat cells were treated with various chemotherapeutic agents. Multiple independently derived Fas-resistant Jurkat lines underwent apoptosis that was indistinguishable from that of the Fas-sensitive parental cells after treatment with etoposide, doxorubicin, topotecan, cisplatin, methotrexate, staurosporine, or gamma-irradiation. These results indicate that antineoplastic treatments induce apoptosis through a Fas-independent pathway even though Fas- and chemotherapy-induced pathways converge on common downstream apoptotic effector molecules.
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PMID:Comparison of apoptosis in wild-type and Fas-resistant cells: chemotherapy-induced apoptosis is not dependent on Fas/Fas ligand interactions. 924 21

Fas-mediated apoptosis results in the activation of caspases, which subsequently cleave cellular substrates that are essential for normal cell viability. In the present study, we show that the Ras-related GTP-binding protein Cdc42 is susceptible to caspase-catalyzed proteolysis in a number of cell lines, including NIH3T3 fibroblasts, human breast cancer cells (e.g. T47D), and COS-7 cells. Both caspase-3 and caspase-7 were able to catalyze the cleavage of Cdc42, whereas caspase-6 and caspase-8 were without effect. The susceptibility to the caspase-stimulated degradation is specific; although Rac can also serve as a caspase substrate, neither Rho nor Ras is degraded. Caspase sensitivity is conferred by a consensus sequence (DXXD) that lies immediately upstream of the Rho insert regions (residues 122-134) of Cdc42 and Rac. The removal of a stretch of residues (120) that includes the insert region or site-directed mutagenesis of either aspartic acid 118 or 121 within a constitutively active background (i.e. Cdc42(F28L)) as well as a wild-type Cdc42 background yields Cdc42 molecules that provide a marked protection against Fas ligand-induced apoptosis. Overall, these results are consistent with a model in which Cdc42 acts downstream of Fas, perhaps to influence the rate of apoptosis, with the ultimate caspase-mediated degradation of Cdc42 then allowing for a maximal apoptotic response.
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PMID:Cdc42 is a substrate for caspases and influences Fas-induced apoptosis. 1127 72

Treatment of human breast carcinoma MCF7 cells with doxorubicin, one of the most active antineoplastic agents used in clinical oncology, induces apoptosis and leads to increases in sphingosine levels. The transient generation of this sphingolipid mediator preceded cytochrome c release from the mitochondria and activation of the executioner caspase-7 in MCF7 cells which do not express caspase-3. Bcl-x(L) overexpression did not affect sphingosine generation whereas it reduced apoptosis triggered by doxorubicin and completely blocked apoptosis triggered by sphingosine. Exogenous sphingosine-induced apoptosis was also accompanied by cytochrome c release and activation of caspase-7 in a Bcl-x(L)-sensitive manner. Furthermore, neither doxorubicin nor sphingosine treatment affected expression of Fas ligand or induced activation of the apical caspase-8, indicating a Fas/Fas ligand-independent mechanism. Our results suggest that a further metabolite of ceramide, sphingosine, may also be involved in mitochondria-mediated apoptotic signaling induced by doxorubicin in human breast cancer cells.
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PMID:Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells. 1131 18

Testicular germ cell cancer is one of the very few cancers that are highly sensitive to and curable by cisplatin-based chemotherapy even in an advanced stage. However, in a few cases resistance to cisplatin occurs and patients subsequently die from progressive disease. The molecular basis for this resistance remains to be determined. Using two cisplatin-sensitive (2102EP and H12.1) and one cisplatin-resistant human testicular germ cell cancer cell line (1411HP), we investigated molecular mechanisms in the induction of apoptosis after cisplatin-treatment focusing on the cleavage and activation of caspase-2, caspase-3, caspase-7, caspase-8, and caspase-9. The cell line 1411HP showed a 3.3-fold cisplatin resistance when compared with the sensitive cell lines 2102EP and H12.1 by IC(90)s, which was treatment schedule independent (2- or 24-h incubation). Cisplatin resistance was associated with substantially decreased apoptosis in vitro and in derived nude mice xenografts as determined by Apo 2.7 detection, DNA-laddering, immunohistochemistry of active caspase-3, and terminal deoxynucleotidyl transferase-mediated nick end labeling assay. Total DNA platination as assessed by ELISA after cisplatin treatment in equimolar doses did not differ between cisplatin-resistant or -sensitive cells. In separate analysis of cells of early and late apoptotic stages, initiation of cisplatin-induced apoptosis appeared to be rather mediated by caspase-9 than by caspase-8. Resistant 1411HP cells failed to activate caspase-9 during the induction of apoptosis after cisplatin treatment at the IC(90) dose. Interestingly, inhibition of caspase-9 in sensitive H12.1 almost completely blocked apoptosis and induced cisplatin resistance to the same extent as in 1411HP so that apoptosis could only be induced by 3.3-fold higher cisplatin doses. Furthermore, in caspase-9 blocked cells, initiation of apoptosis occurred in a caspase-9 independent manner accompanied by activation of caspase-2 and caspase-3, which are intrinsic characteristics of resistant 1411HP cells. Failure of caspase-9 activation and cisplatin resistance was independent of the expression of p53, Bcl-2 family proteins, Fas receptor, and Fas ligand. In conclusion, failure of activation of the caspase-9 pathway induces a higher cellular threshold for cisplatin-mediated induction of apoptosis in testicular cancer cells. However, this higher threshold can be overcome by higher cisplatin doses, conceivably by using an alternate, caspase-9-independent apoptotic pathway. This supports the current clinical strategy of high-dose chemotherapy in patients with chemorefractory germ cell tumors. However, additional defining and eventually targeting the exact molecular mechanism blocking caspase-9 activation might lead to more selective therapeutic approaches to overcome cisplatin resistance in germ cell cancer.
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PMID:Failure of activation of caspase-9 induces a higher threshold for apoptosis and cisplatin resistance in testicular cancer. 1254 10

Apoptosis occurs during the isolation and even short-term storage and culture of hepatocytes, and in the pathogenesis of liver diseases, such as hepatic failure and hepatitis. Therapeutic hypothermia has beneficial effects in experimental models of fulminant hepatic failure. The mechanisms underlying the potential benefits of mild hypothermia on the liver have not been well investigated. We examined the effects of temperature on soluble Fas ligand-induced apoptosis in freshly isolated mouse hepatocytes. Decreasing the culture temperature from 37 degrees C to 32 degrees C produced significant suppression of Fas-mediated apoptosis in cultured hepatocytes over a 12-h period. This observation was supported by cell morphology, flow cytometry analysis of cellular DNA content, and Annexin V-FITC staining of membrane phosphatidylserine translocation. In hypothermic conditions, Fas-mediated cytochrome c release from mitochondria of hepatocytes and the proximate downstream activation of caspase-9 were suppressed under mild hypothermic conditions. Effector caspase-7 activity was also inhibited at 32 degrees C. In contrast, the activation of initiator caspase-8 and cleavage of Bid were not affected after Fas-ligand stimulation. These findings suggest that mild hypothermia suppresses Fas-mediated apoptosis of liver cells by the partial inhibition of signaling events including mitochondrial damage, cytochrome c release, and subsequent apoptosome formation and effector caspase activation.
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PMID:Hypothermia inhibits Fas-mediated apoptosis of primary mouse hepatocytes in culture. 1564 37

Isoliquiritigenin (ISL), a simple chalcone derivative, 4,2',4'-trihydroxychalcone, found in licorice, shallot and bean sprouts, has been reported to have chemoprotective effects. To examine the effects of ISL on the growth of prostate cancer cells, we cultured MAT-LyLu (MLL) rat and DU145 human prostate cancer cells with various concentrations (0-20 micromol/L) of ISL. Treatment of the cells with increasing concentrations of ISL led to dose-dependent decreases in the viable cell numbers in both DU145 and MLL cells (P<.05). Hoechst 33258 dye staining of condensed nuclei and annexin V binding to surface phosphatidylserine revealed increased numbers of apoptotic cells after ISL treatment. Western blot analysis revealed that ISL increased the levels of membrane-bound Fas ligand (FasL), Fas, cleaved casapse-8, truncated Bid (tBid), Bax and Bad in DU145 cells (P<.05). Isoliquiritigenin increased the percentage of cells with depolarized mitochondrial membranes, in a concentration-dependent manner (P<.05). Isoliquiritigenin induced the release of cytochrome c and Smac/Diablo from the mitochondria into the cytoplasm (P<.05). Isoliquiritigenin dose-dependently increased the levels of cleaved caspase-9, caspase-7, caspase-3 and poly(ADP-ribose) polymerase (P<.05). The present results indicate that ISL inhibits prostate cancer cell growth by the induction of apoptosis, which is mediated through mitochondrial events, which are associated with an evident disruption of the mitochondrial membrane potential, and the release of cytochrome c and Smac/Diablo, and the activation of caspase-9.
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PMID:Isoliquiritigenin induces apoptosis by depolarizing mitochondrial membranes in prostate cancer cells. 1651 40

Acrolein, which is a highly reactive alpha,beta-unsaturated aldehyde generated by lipid peroxidation, can affect cells and tissues and cause various disorders. Increased levels of unsaturated aldehydes play an important role in the pathogenesis of a number of human diseases such as Alzheimer's disease, atherosclerosis and diabetes. Acrolein is a highly ubiquitous toxic environmental pollutant. Because of human exposure, there is a need for investigating the mechanisms involved in acrolein toxicity at the cellular and molecular levels. Acrolein can induce cell death by apoptosis, although the mechanisms are not entirely clear. The present study investigates whether mitogen-activated protein kinases (MAPKs) play a role in activation of apoptosis by acrolein. Our findings show that acrolein-mediated apoptosis is in fact MAPK-dependent in Chinese hamster ovary cells. The MAP family kinases, including ERK and p38 kinase, and the transcription factor c-Jun were all activated by phosphorylation after 1 h exposure to acrolein. Phosphorylation of ERK and p38 kinases and their blockade by an ERK inhibitor, U0126, or a p38 inhibitor, SB203580, respectively, suggested that activation of apoptosis by acrolein is ERK- and p38-dependent. Thus, blockade of ERK and p38 inhibited chromatin condensation, caspase-7 and -9 activation as well as ICAD cleavage induced by acrolein. JNK and AKT kinases seem to be implicated in survival pathways against acrolein insult, since their respective inhibitors, SP600125 and LY294002/Wortmannin switched the mode of cell death from apoptosis to total necrosis. Finally, acrolein induced phosphorylation of the pro-apoptotic factor p53 which is responsible for transcription of pro-apoptotic factors such as Bax and Fas ligand. These results provide new information demonstrating the implication of MAPKs and AKT in acrolein-induced apoptosis, and this information may be useful for understanding the pathogenesis of a number of tissue diseases and environmental toxicity in response to acrolein.
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PMID:P38 and ERK mitogen-activated protein kinases mediate acrolein-induced apoptosis in Chinese hamster ovary cells. 1719 91

Avian H5N1 influenza virus causes a remarkably severe disease in humans, with an overall case fatality rate of greater than 50%. Human influenza A viruses induce apoptosis in infected cells, which can lead to organ dysfunction. To verify the role of H5N1-encoded NS1 in inducing apoptosis, the NS1 gene was cloned and expressed in human airway epithelial cells (NCI-H292 cells). The apoptotic events posttransfection were examined by a terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick-end-labeling assay, flow cytometric measurement of propidium iodide, annexin V staining, and Western blot analyses with antibodies specific for proapoptotic and antiapoptotic proteins. We demonstrated that the expression of H5N1 NS1 protein in NCI-H292 cells was sufficient to induce apoptotic cell death. Western blot analyses also showed that there was prominent cleavage of poly(ADP-ribose) polymerase and activation of caspase-3, caspase-7, and caspase-8 during the NS1-induced apoptosis. The results of caspase inhibitor assays further confirmed the involvement of caspase-dependent pathways in the NS1-induced apoptosis. Interestingly, the ability of H5N1 NS1 protein to induce apoptosis was much enhanced in cells pretreated with Fas ligand (the time posttransfection required to reach >30% apoptosis was reduced from 24 to 6 h). Furthermore, 24 h posttransfection, an increase in Fas ligand mRNA expression of about 5.6-fold was detected in cells transfected with H5N1 NS1. In conclusion, we demonstrated that the NS1 protein encoded by avian influenza A virus H5N1 induced apoptosis in human lung epithelial cells, mainly via the caspase-dependent pathway, which encourages further investigation into the potential for the NS1 protein to be a novel therapeutic target.
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PMID:Avian influenza virus A/HK/483/97(H5N1) NS1 protein induces apoptosis in human airway epithelial cells. 1819 56

White adipose tissue is intimately involved in the regulation of immunity and inflammation. We reported that human mesenteric preadipocytes express the substance P (SP)-mediated neurokinin-1 receptor (NK-1R), which signals proinflammatory responses. Here we tested the hypothesis that SP promotes proliferation and survival of human mesenteric preadipocytes and investigated responsible mechanism(s). Preadipocytes were isolated from mesenteric fat biopsies during gastric bypass surgery. Proliferative and antiapoptotic responses were delineated in 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), bromodeoxyuridine (BrdU), caspase-3, and TUNEL assays, as well as Western immunoanalysis. SP (10(-7) M) increased MTS and proliferation (BrdU) and time dependently (15-30 min) induced Akt, EGF receptor, IGF receptor, integrin alphaVbeta3, phosphatidylinositol 3-kinase, and PKC-theta phosphorylation. Furthermore, pharmacological antagonism of Akt and PKC-theta activation significantly attenuated SP-induced preadipocyte proliferation. Exposure of preadipocytes to the proapoptotic Fas ligand (FasL, 100 microM) resulted in nuclear DNA fragmentation (TUNEL assay), as well as increased cleaved poly (ADP-ribose) polymerase, cleaved caspase-7, and caspase-3 expression. Cotreatment with SP almost completely abolished these responses in a NK-1R-dependent fashion. SP (10(-7) M) also time dependently stimulated expression 4E binding protein 1 and phosphorylation of p70 S6 kinase, which increased protein translation efficiency. SP increases preadipocyte viability, reduces apoptosis, and stimulates proliferation, possibly via cell cycle upregulation and increased protein translation efficiency. SP-induced proliferative and antiapoptotic pathways in fat depots may contribute to development of the creeping fat and inflammation characteristic of Crohn's disease.
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PMID:Substance P promotes expansion of human mesenteric preadipocytes through proliferative and antiapoptotic pathways. 1928 77

Acrolein, a highly reactive alpha,beta-unsaturated aldehyde, is an omnipresent environmental pollutant. Chronic and acute human exposures occur through exogenous and endogenous sources, including food, vapors of overheated cooking oil, house and forest fires, cigarette smoke, and automobile exhaust. Acrolein is a toxic byproduct of lipid peroxidation, which has been implicated in pulmonary, cardiac, and neurodegenerative diseases. This study shows that p53 is an initiating factor in acrolein-induced death receptor activation during apoptosis in A549 human lung cells. Exposure of cells to acrolein (0-50 micromol/L) mainly caused apoptosis, which was manifested by execution phase events such as condensation of nuclear chromatin, phosphatidylserine externalization, and poly(ADP-ribose) polymerase (PARP) cleavage. Levels of necrosis (approximately 5%) were low. Acrolein triggered the death receptor pathway of apoptosis, causing elevation of Fas ligand (FasL) and translocation of adaptor protein Fas-associated death domain to the plasma membrane. Acrolein caused activation of caspase-8, caspase-2, caspase-7, and the cross-talk pathway mediated by Bid cleavage. Activation of p53 and increased expression of p53-upregulated modulator of apoptosis (PUMA) occurred in response to acrolein. FasL upregulation and caspase-8 activation were decreased by p53 inhibitor pifithrin-alpha and antioxidant polyethylene glycol catalase. These findings increase our knowledge about the induction of cell death pathways by acrolein, which has important implications for human health.
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PMID:Acrolein induces apoptosis through the death receptor pathway in A549 lung cells: role of p53. 2039


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