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)

Chemoresistance has been one of the major problems in anticancer therapy. In our effort to find a potential molecular target for overcoming the chemoresistance in prostate cancer, a promising anticancer drug trichostatin A (TSA) induced cell death was found to be compromised by enhanced NF-kappaB activation in 267B1/K-ras human prostate epithelial cancer cells. However, both the NF-kappaB activation and chemoresistance were reduced by pretreatment with proteasome inhibitor-I (ProI), accompanied by accumulations of both IkappaBalpha and p65/RelA (but not p50/NF-kappaB1) in the cytoplasm. Clonogenic cell survival and soft agar assays further confirmed the increased TSA chemosensitivity of 267B1/K-ras cells by ProI treatment. Moreover, dominant negative mutant of IKKbeta, IkappaBalpha and p65 enhanced the chemosensitization, too. Unexpectedly, using LY294002 and PD98059, phosphatidylinositol-3-kinase and mitogen-activated protein kinase were also implied in TSA chemoresistance through NF-kappaB activation, while these compounds had showed no effect on radiosensitization in the cells. On the other hand, together with TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay, activations of caspase-8 and caspase-3 by TSA and ProI were noticed, suggesting the involvement of apoptotic process in chemosensitization of 267B1/K-ras cells. Altogether, these results suggest that blocking the NF-kappaB activation pathway could be an efficient target for improving the TSA chemosensitization and applying to the development of anticancer therapeutics in Ki-Ras-overexpressing tumorigenic cells, including prostate cancer.
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PMID:NF-kappaB inhibition increases chemosensitivity to trichostatin A-induced cell death of Ki-Ras-transformed human prostate epithelial cells. 1677 37

Diterpenoids isolated from Labiatae family herbs have strong antitumor activities with low toxicity. In this study, Eriocalyxin B (EriB), a diterpenoid extracted from Isodon eriocalyx, was tested on human leukemia/lymphoma cells and murine leukemia models. Acute myeloid leukemia cell line Kasumi-1 was most sensitive to EriB. Significant apoptosis was observed, concomitant with Bcl-2/Bcl-XL downregulation, mitochondrial instability and caspase-3 activation. AML1-ETO oncoprotein was degraded in parallel to caspase-3 activation. EriB-mediated apoptosis was associated with NF-kappaB inactivation by preventing NF-kappaB nuclear translocation and inducing IkappaBalpha cleavage, and disturbance of MAPK pathway by downregulating ERK1/2 phosphorylation and activating AP-1. Without affecting normal hematopoietic progenitor cells proliferation, EriB was effective on primary t(8;21) leukemia blasts and caused AML1-ETO degradation. In murine t(8;21) leukemia models, EriB remarkably prolonged the survival time or decreased the xenograft tumor size. Together, EriB might be a potential treatment for t(8;21) leukemia by targeting AML1-ETO oncoprotein and activating apoptosis pathways.
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PMID:Eriocalyxin B induces apoptosis of t(8;21) leukemia cells through NF-kappaB and MAPK signaling pathways and triggers degradation of AML1-ETO oncoprotein in a caspase-3-dependent manner. 1677 32

Naringenin (NGEN), a flavonoid, has shown cytotoxicity in various human cancer cell lines and inhibitory effects on tumor growth. In this study, we investigated the apoptosis induced by NGEN via the activation of NF-kappaB and necrosis involving the loss of ATP in human promyeloleukemia HL-60 cells. Exposure to NGEN induced apoptosis dose-dependently up until 0.5mM, but not at 1mM as demonstrated by a quantitative analysis of nuclear morphological change and flow cytometric analysis. An extensive inhibitor for caspases, abolished the NGEN-induced apoptosis. The apoptosis-triggering concentration of NGEN was shown to markedly promote the activation of caspase-3, and slightly promote that of caspase-9, but had no effect on caspase-8. NGEN-induced apoptosis caused by induction of specific NF-kappaB-binding activity and involving the degradation of IkappaBalpha. Incubation with a high concentration of NGEN (1mM) reduced intracellular ATP levels, but no change was observed at lower concentrations. NGEN increased dose-dependently hyperpolarization of mitochondrial membrane potential. This result indicates a common pathway to apoptosis and necrosis by NGEN. One of the mechanisms by NGEN-induced apoptosis may relate to the activation of NF-kappaB that correlates with degradation of IkappaBalpha. Induction of necrosis by NGEN suggests causing by intracellular ATP depletion and mitochondria dysfunctions.
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PMID:Naringenin-induced apoptosis via activation of NF-kappaB and necrosis involving the loss of ATP in human promyeloleukemia HL-60 cells. 1686 Sep 49

Whether resveratrol, a component of red grapes, berries, and peanuts, could suppress the proliferation of multiple myeloma (MM) cells by interfering with NF-kappaB and STAT3 pathways, was investigated. Resveratrol inhibited the proliferation of human multiple myeloma cell lines regardless of whether they were sensitive or resistant to the conventional chemotherapy agents. This stilbene also potentiated the apoptotic effects of bortezomib and thalidomide. Resveratrol induced apoptosis as indicated by accumulation of sub-G(1) population, increase in Bax release, and activation of caspase-3. This correlated with down-regulation of various proliferative and antiapoptotic gene products, including cyclin D1, cIAP-2, XIAP, survivin, Bcl-2, Bcl-xL, Bfl-1/A1, and TRAF2. In addition, resveratrol down-regulated the constitutive activation of AKT. These effects of resveratrol are mediated through suppression of constitutively active NF-kappaB through inhibition of IkappaBalpha kinase and the phosphorylation of IkappaBalpha and of p65. Resveratrol inhibited both the constitutive and the interleukin 6-induced activation of STAT3. When we examined CD138(+) plasma cells from patients with MM, resveratrol inhibited constitutive activation of both NF-kappaB and STAT3, leading to down-regulation of cell proliferation and potentiation of apoptosis induced by bortezomib and thalidomide. These mechanistic findings suggest that resveratrol may have a potential in the treatment of multiple myeloma.
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PMID:Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. 1716 50

The regulatory subunit IKKgamma/NEMO is crucial for skin development and function and although devoid of kinase activity, loss of IKKgamma function completely abolishes the activation of NF-kappaB by all pro-inflammatory cytokines. To inhibit the IkappaB kinase (IKK) complex in keratinocytes, we have used a dominant negative approach by generating stable transfectants of an N-terminal deletion of IKKgamma (IKKgamma-DN97) that uncouples formation of the IKK complex. Expression of this mutant in PB keratinocytes (PB-IKKgamma-DN97) delayed growth kinetics, caused morphological changes and dramatically augmented apoptosis even in the absence of pro-apoptotic stimuli, as determined by cell morphology, TUNEL and caspase-3 cleavage. Moreover, in PB-IKKgamma-DN97 cells, TNF-alpha and IL-1 treatment failed to induce degradation of IkappaBalpha, phosphorylation of p65 on Ser 536 and nuclear translocation which, consequently, reduced kappaB-binding activity. In PB-IKKgamma-DN97 cells, accumulation of IkappaBalpha correlated with a downregulation of AKT activity and an increase of PTEN protein levels whereas pro-apoptotic p53 target genes Bax and Puma were upregulated. These effects were most likely mediated through IKK since coexpression of the wild-type form of IKKgamma in keratinocytes partially reversed apoptosis and reduced PTEN expression. Thus, our data suggest a negative cross-talk mechanism involving PTEN and NF-kappaB, critical for the anti-apoptotic role of NF-kappaB in keratinocytes.
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PMID:Deletion of the N-terminus of IKKgamma induces apoptosis in keratinocytes and impairs the AKT/PTEN signaling pathway. 1718 72

In this report, the mechanism of the antitumor activities of Kushen flavonoids (KS-Fs) were explored. KS-Fs and kurarinone (Kur), a single flavonoid compound, were able to induce apoptosis of H460 and Eca-109 cells in vitro and H460 cells in vivo. The apoptosis inducing effect was enhanced in the presence of Taxol. In H460 xenograft mice treated with Kur, down-regulation of Bcl-2 and up-regulation of caspase 8 and caspase 3 in tumors were observed by immunohistochemical staining. In addition, KS-Fs and Kur were able to inhibit TNFalpha-induced NF-kappaB activation in 293 cells mediated by the decreased IkappaBalpha phosphorylation. Further the effects of KS-Fs and Kur on multiple receptor tyrosine kinase activities were explored. In cell-based assays, KS-Fs and Kur inhibited the EGF-induced EGF receptor phosphorylation in A431 cells and a constitutively activated Her-2 in MDA-MB-453s cells. In enzymatic assays, KS-Fs and Kur inhibited KDR, but not PDGF BR activities. In A431 xenograft mice treated with Kur, an inhibition of EGF receptor phosphorylation in tumors was observed. These results reveal a novel mechanism by which KS-Fs induces apoptosis in tumors by acting on multiple cellular targets including the inhibition of NF-kappaB activation and multiple receptor tyrosine kinase activities.
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PMID:Kushen flavonoids induce apoptosis in tumor cells by inhibition of NF-kappaB activation and multiple receptor tyrosine kinase activities. 1718 93

Aflatoxins (AF) are contaminants of improperly stored foods; they are potent genotoxic and carcinogenic compounds, exerting their effects through damage to DNA. They can also induce mutations that increase oxidative damage. The goal of this study was to evaluate the possibility that a third mechanism could be involved in the carcinogenic action of aflatoxins, namely, direct binding to key enzymes involved in the regulatory pathways of the cell cycle, thereby modulating enzyme functionality. The 20S constitutive and immunoproteasome peptidase and proteolytic activities were assayed in the presence of aflatoxins B1, G1 and M1. All three toxins activated multiple peptidase activities of the proteasome. Aflatoxin (AF) M1 was the most potent activator of proteasome activity, while the constitutive 20S proteasome was specifically stimulated by AFG1. Furthermore, the effects of AFB1 on cultured hepatoma cells were investigated and the various proteasomal activities determined with cell lysates were differently affected. Taking into account the key role of the proteasome in cellular defense against oxidative stress, the carbonyl group content and the activities of antioxidant enzymes in cell lysates were analyzed. The proapoptotic effect of AFB1 was also investigated by measuring caspase-3 activity and cellular levels of p27 and IkappaBalpha.
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PMID:Binding of aflatoxins to the 20S proteasome: effects on enzyme functionality and implications for oxidative stress and apoptosis. 1721 55

This study investigated radioresistance mechanisms in the doxorubicin-resistant acute myelogenous leukemia (AML)-2/DX100. AML-2/DX100 also showed resistance to radiation. AML-2/DX100 characterized by down-regulated catalase expression was supersensitive to exogenous hydrogen peroxide whereas they increased defense mechanisms against endogenous reactive oxygen species (ROS) as compared with AML-2/WT. In AML-2/WT, radiation increased Bax expression and its translocation to mitochondria but had little effect on translocation of Bcl-2 and consequently induced the release of cytochrome c from the mitochondria with the subsequent caspase-3 activation. On the contrary, in AML-2/DX100, radiation neither increased Bax expression nor its translocation to mitochondria while it increased Bcl-2 translocation to mitochondria. A specific p38 MAPK inhibitor SB203580 increased radioresistance in AML-2/WT but little in AML-2/DX100. It inhibited radiation-induced Bax translocation in AML-2/WT but not in AML-2/DX100, indicating that p38 MAPK is working after irradiation in AML-2/WT but not in AML-2/DX100. Electrophoretic mobility shift assay and Western blot analysis revealed that NF-kappaB in AML-2/DX100 was more activated with degradation of cytosolic IkappaBalpha than was that of AML-2/WT. cDNA microarray showed that Bfl-1/A1 and granzyme H in AML-2/DX100 were highly up-regulated (6.21-fold) and down-regulated (6.49-fold), respectively, as compared with each of AML-2/WT, which were confirmed by RT-PCR assay. Taken together, these results indicate that radioresistance mechanisms of AML-2/DX100 could be related to alterations in ROS-scavenging activity, in mitochondrial translocation of Bax and Bcl-2, and in expression of pro-apoptotic (granzyme H) and anti-apoptotic (Bfl-1/A1) genes. It has been shown that balance of p38 MAPK and NF-kappaB signals is a determinant in radiosensitivity of AML-2/WT and AML-2/DX100.
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PMID:Balance of NF-kappaB and p38 MAPK is a determinant of radiosensitivity of the AML-2 and its doxorubicin-resistant cell lines. 1721 10

This study evaluated the effects of overexpression of wild-type (WT) or phosphatase-deficient (PD) mutant of an osteoclastic protein-tyrosine phosphatase (PTP-oc) in RAW/C4 cells. Osteoclast-like cells derived from WT-PTP-oc overexpressing clones increased, while those derived from PD-PTP-oc expressing clones decreased, their resorption activity. WT-PTP-oc clones had lower apoptosis, lower caspase 3/7 activity, reduced c-Src tyr-527 phosphorylation (PY527) and IkappaBalpha cellular levels, and increased NFkappaB activation and JNK phosphorylation. Overexpression of PD-PTP-oc or PTP-oc siRNA treatment increased apoptosis, caspase 3/7 activity, PY527 and IkappaBalpha levels, and decreased NFkappaB and JNK2 activation. Inhibition of the c-Src kinase blocked the PTP-oc-mediated NFkappaB and JNK2 activation. Blocking the NFkappaB activation had no effect on the JNK2 activation. Inhibiting the NFkappaB and/or JNK2 pathway prevented the PTP-oc-mediated reduction in apoptosis. In conclusion, PTP-oc activates osteoclast activity in part by promoting osteoclast survival through the PTP-oc-mediated c-Src-dependent activation of NFkappaB and JNK2.
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PMID:A transmembrane osteoclastic protein-tyrosine phosphatase regulates osteoclast activity in part by promoting osteoclast survival through c-Src-dependent activation of NFkappaB and JNK2. 1740 Jan 76

Apoptosis plays a critical role in intestinal mucosal homeostasis. We previously showed that the bile salt taurodeoxycholate has a beneficial effect on the intestinal mucosa through an increase in resistance to apoptosis mediated by nuclear factor (NF)-kappaB. The current study further characterizes the effect of bile salts on intestinal epithelial cell susceptibility to apoptosis and determines if the X-linked inhibitor of apoptosis protein (XIAP) regulates bile salt-induced resistance to apoptosis. Exposure of normal intestinal epithelial cells (IEC-6) to the conjugated bile salts taurodeoxycholate (TDCA) and taurochenodeoxycholate (TCDCA) resulted in an increase in resistance to tumor necrosis factor (TNF)-alpha and cycloheximide (CHX)-induced apoptosis, and NF-kappaB activation. Treatment with TDCA and TCDCA resulted in an increase in XIAP expression. Specific inhibition of NF-kappaB by infection with an adenoviral vector that expresses the IkappaBalpha super-repressor (IkappaBSR) prevented the induction of XIAP expression and the bile salt-mediated resistance to apoptosis. Treatment with the specific XIAP inhibitor Smac also overcame this increase in enterocyte resistance to apoptosis. Bile salts inhibited formation of the active caspase-3 from its precursor procaspase-3. Smac prevented the inhibitory effect of bile salts on caspase-3 activation. These results indicate that bile salts increase intestinal epithelial cell resistance to apoptosis through NF-kappaB-mediated XIAP expression. Bile salt-induced XIAP mediates resistance to TNF-alpha/CHX-induced apoptosis, at least partially, through inhibition of caspase-3 activity. These data support an important beneficial role of bile salts in regulation of mucosal integrity. Decreased enterocyte exposure to luminal bile salts, as occurs during starvation and parenteral nutrition, may have a detrimental effect on mucosal integrity.
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PMID:Bile salts induce resistance to apoptosis through NF-kappaB-mediated XIAP expression. 1743 49

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