Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

beta-Lapachone, a novel anti-neoplastic drug, induces various cancer cells to undergo apoptosis. In a previous report, we showed that beta-lapachone-induced apoptosis of HL-60 cells is mediated by oxidative stress. However, in the present study, we found that beta-lapachone-induced apoptosis of human prostate cancer (HPC) cells may be independent of oxidative stress. In contrast to the 10-fold beta-lapachone-induced increase in H(2)O(2) production seen in HL-60 cells, only a 2- to 4-fold increase was observed in HPC cells. N-acetyl-L-cysteine (NAC), a thiol antioxidant, inhibited the apoptosis in DU145 cells after 12 h exposure to beta-lapachone. Nonetheless, NAC, along with other antioxidants, failed to exert similar effect in HPC cells subjected to beta-lapachone treatment for 24 h. Under this premise, we suggest that the oxidative stress may not play a crucial role in beta-lapachone-mediated HPC cell apoptosis. Here we demonstrate that damage to genomic DNA is the trigger for the apoptosis of HPC cells induced by beta-lapachone. According to our results, beta-lapachone stimulates DNA dependent kinase expression and poly(ADP-ribose) polymerase cleavage in advance of significant morphological changes. beta-Lapachone promotes the expression of cyclin-dependent kinase (cdk) inhibitors (p21(WAF1) and p27(Kip1)), induces bak expression, and subsequently stimulates the activation of caspase-7 but not of caspase-3 or caspase-8 during the apoptosis of HPC cells. Taken together, these results suggest that the signaling pathway involving the beta-lapachone-induced apoptosis of HPC cell may be by DNA damage, induction of cdk inhibitors (p21 and p27), and then subsequent stimulation of caspase-7 activation.
 ...
PMID:Induction of CDK inhibitors (p21(WAF1) and p27(Kip1)) and Bak in the beta-lapachone-induced apoptosis of human prostate cancer cells. 1125 23

UVB from solar radiation is both an initiating and promoting agent for skin cancer. We have found that primary human keratinocytes undergo an apoptotic response to UVB. To determine whether these responses are altered during the course of immortalization, we examined markers of apoptosis in primary human foreskin keratinocytes (HFK) transduced with either a retroviral vector expressing the E6 and E7 genes of HPV-16 or with empty vector alone (LXSN-HFK). Whereas LXSN-HFK as well as early passage keratinocytes expressing HPV-16 E6 and E7 (p7 E6/7-HFK) were both moderately responsive to UVB irradiation, late passage-immortalized keratinocytes (p27 E6/7-HFK) were exquisitely sensitive to UVB-induced apoptosis. After exposure to UVB, enhanced annexin V-positivity and internucleosomal DNA fragmentation were observed in p27 E6/7-HFK compared with either LXSN- or p7 E6/7-HFK. Caspase-3 fluorometric activity assays as well as immunoblot analysis with antibodies to caspase-3 and poly(ADP-ribose) polymerase revealed elevated caspase-3 activity and processing at lower UVB doses in p27 E6/7-HFK compared with LXSN- or p7 E6/7-HFK. In addition, the caspase inhibitor DEVD-CHO reduced the apoptotic response and increased survival of all three HFK types. Immunoblot analysis revealed that caspase-8 was activated in all three cell types, but caspase-9 was only activated in p27 E6/7-HFK. Cell cycle analysis further showed that only p27 E6/7-HFK exhibit G(2)/M accumulation that is enhanced by UVB treatment. This accumulation was associated with a rapid down-regulation of Bcl-2 in these cells. The immortalization process subsequent to the expression of HPV E6 and E7 may therefore determine UVB sensitivity by switching the mode of apoptosis from a caspase-8 to a Bcl-2-caspase-9-mediated pathway of apoptosis.
 ...
PMID:HPV-16 E6/7 immortalization sensitizes human keratinocytes to ultraviolet B by altering the pathway from caspase-8 to caspase-9-dependent apoptosis. 1197 23

Monensin, an Na(+) ionophore, regulates many cellular functions including apoptosis. However, there has been no report about the antitumoral effect of monensin on acute myelogenous leukemia (AML). Here, we investigated the antiproliferative effect of monensin on AML cells in vitro and in vivo. Monensin efficiently inhibited the proliferation of all of 10 AML cell lines, with IC(50) of about 0.5 microM. DNA flow cytometric analysis indicated that monensin induced a G(1) and/or a G(2)-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of monensin, we examined the effect of monensin on cell cycle-related proteins in HL-60 cells. The levels of CDK6, cyclin D1 and cyclin A were decreased. In addition, monensin not only increased the p27 level but also enhanced its binding with CDK2. Furthermore, the activities of CDK2- and CDK6-associated kinases reduced by monensin were associated with hypophosphorylation of Rb protein. Monensin also induced apoptosis in AML cells including HL-60 cells. The apoptotic process of HL-60 cells was associated with changes in Bax, caspase-3, caspase-8 and mitochondria transmembrane potential (Deltapsi(m)). In particular, monensin (i.p. at a dose of 8 mg/kg thrice weekly) significantly reduced the tumor size of BALB/c mice that were inoculated s.c. with its derived cell line, WEHI-3BD cells (69% growth inhibition relative to control group; p < 0.05). Tumors from monensin-treated mice exhibited increased apoptosis, and these tumor were immunohistochemically more stained with Bax, Fas and p53 antibodies than control tumors. In conclusion, this is the first report that monensin potently inhibits the proliferation of AML cells.
 ...
PMID:Monensin-mediated growth inhibition in acute myelogenous leukemia cells via cell cycle arrest and apoptosis. 1220 73

We have investigated the hepatic response of female C57BL/6J wild-type and p53(+/-) hemizygous mice to genotoxic levels of diethylstilbestrol (DES) using cell cycle and apoptosis-focussed cDNA expression arrays. DES induced the expression of 12 genes (bad, bax, bcl-x, caspase-1, p53, cyclin D3, GADD45, p21, p15, p27, p57 and Skp1) and down-regulated the expression of eight genes (bcl-2, caspase-2, caspase-7, caspase-8, E124, iNOS, mdm2 and NFkappab1) at twofold or greater levels. Taken together, these changes were strongly reflective of the induction of apoptosis in the livers of DES-treated mice. Of those genes showing the greatest changes in response to DES, p53, p21 and p57 were expressed at 2.1, 1.7 and 1.6 times greater (respectively) in wild-type mice as compared with p53(+/-) hemizygous mice. Differences in p53, p21 and bax expression were confirmed by RT-PCR and we conclude that the compromised response of p53(+/-) mice is likely to play a central role in the earlier appearance of tumours in this model, following exposure to genotoxic carcinogens.
 ...
PMID:A comparison of gene expression changes in response to diethylstilbestrol treatment in wild-type and p53+/- hemizygous knockout mice using focussed arrays. 1250 44

The hepatic stellate cell (HSC), the pericyte of the liver sinusoids belongs to the mesenchymal cells of the liver. Damaging noxae induce a transformation from the quiescent (vitamin A-storing cell) to the activated (connective tissue-producing cell) state. The balance between proapoptotic and surviving factors decides about the fate of the activated HSC. Interferon-alpha (IFN-alpha) has been shown to elicit antiproliferative and/or antifibrogenic effects in various cell types of mesenchymal origin. We therefore investigated the effect of IFN-alpha on primary cultured rat HSC in their quiescent (day 2) and activated state (day 7). IFN-alpha significantly inhibited spontaneous apoptosis in activated HSC in vitro and simultaneously inhibited cell cycle progression by inducing a G1 arrest. The effect of IFN-a is not accompanied by a modulation of CD95, CD95L, p53, p21(WAF1), p27, bcl-2, bcl-xL, bax, NFkappaB, or IkappaB gene expression. Surprisingly, the IFN-alpha effect could be abolished completely by blocking JAK2 activity or JAK2 translation. The downregulating effect of IFN-alpha on the activity of caspase-8 and caspase-3 could also be neutralized using tyrphostin AG490 or JAK-2 antisense. Taken together IFN-alpha inhibits apoptosis of activated HSC by activation of JAK2 which inhibits the caspase-8 apoptosis pathway.
 ...
PMID:Antiapoptotic effect of interferon-alpha on hepatic stellate cells (HSC): a novel pathway of IFN-alpha signal transduction via Janus kinase 2 (JAK2) and caspase-8. 1260 46

The activated hepatic stellate cell (HSC) is an important fibrogenic cell type of the liver. Interferon-alpha (IFN-alpha) has recently been shown to elicit an antiapoptotic effect on activated HSC by a JAK-2-dependent inhibition of caspase-8 activation. As JAK-2 has so far been shown to be a member of the IFN-gamma signal transduction pathway we studied the effect of IFN-gamma on apoptosis as well as on its signaling in primary cultured rat HSC. IFN-gamma elicited a proapoptotic effect in activated HSC. The combination of both, IFN-gamma and IFN-alpha, however, completely cancelled each other's effect. No effect of the two cytokines on major members of apoptosis-regulating systems (CD95, CD95L, bcl-2, bax, bcl-xL, p53, p21WAF1, p27, NFkappaB) could be observed. Western Blot analysis revealed that gene expression of the chaperone HSP70 was found to be downregulated by IFN-gamma but upregulated by IFN-alpha. The effect could be abrogated by administration of both. After transfection of activated HSC with a pCMV-HSP70 M expression vector the proapoptotic effect of IFN-gamma was cancelled. Using HSP70 antisense, the antiapoptotic effect of IFN-alpha was cancelled as well. However IFN-gamma had no effect on upregulation of JAK-2 and pJAK-2 by IFN-alpha. Taken together IFN-gamma and IFN-alpha exert opposite effects on apoptosis in HSC. This effect is mediated by their counteracting effect on HSP70 expression which acts antiapoptotic at the level of caspase-8.
 ...
PMID:Interferon-gamma acts proapoptotic on hepatic stellate cells (HSC) and abrogates the antiapoptotic effect of interferon-alpha by an HSP70-dependant pathway. 1554 Apr 63

Substantial evidence exists to support a role for RhoA signaling in adhesion and cytoskeletal reorganization, while relatively less is known about the participation of RhoA on cell survival. We provide evidence that RhoA functions as a differential modulator of apoptosis induced by anticancer agents. Specifically, both RhoA and caRhoA induce statistically significant resistance to statin, etoposide, 5-FU and taxol while increasing sensitivity to vincristine (all p<0.001). The IC50 values for statin, etoposide, 5-fluorouracil (5-FU) and taxol in caRhoA transfectant were 8.70+/-0.74, 4.08+/-0.12, 4.12+/-0.12 microg/ml and 3.84+/-0.16 ng/ml, respectively, whereas the respective IC50 values in the mock-transfected control were 3.40+/-0.21, 1.12+/-0.06, 1.21+/-0.06 microg/ml and 2.84+/-0.15 ng/ml. This represented a 2.6-, 3.5-, 3.2- and 1.4-fold resistance to statin, etoposide, 5-FU and taxol, respectively. In contrast, caRhoA increased sensitivity to vincristine, decreasing IC50 values from 4.61+/-0.46 to 3.73+/-0.44 ng/ml (p<0.001). Western blot analysis demonstrated that RhoA mediates induction of E2F-1, Cdk2 and PCNA, accompanying concurrent reduction in p21 and p27. However, cleavage assays of poly (ADP-ribose) polymerase, BID, caspase-8 and caspase-3 indicate that the cell growth modulation mediated by RhoA in response to these anticancer agents occurs through the inhibition of apoptosis. Taken together, these results indicate that RhoA differentially modulates cancer cell death depending on the anticancer agent.
 ...
PMID:Differential effects of RhoA signaling on anticancer agent-induced cell death. 1564 15

Histone deacetylase (HDAC) inhibitors have both apoptotic and differentiating effects on various tumor cells. However, the mechanisms underlying the effect of HDAC inhibitors remain unclear. In this study, we investigated the function of anti-proliferative effects of HDAC inhibitors, N-butyric acid and trichostatin A, on human malignant glioma cell lines, U251-MG and D54. MTT assay showed a dose-dependent inhibition of cellular proliferation in both cell lines. Cell cycle analysis revealed increased sub-G1 population in both lines, and G1 arrest only in U251-MG cells. Induction of apoptosis was also supported by the occurrence of DNA fragmentation in tumor cells treated with HDAC inhibitors. Furthermore, caspase inhibition assay indicated that HDAC inhibitor-induced apoptosis was caspase-dependent. Neither mitochondrial membrane potential nor the expression of caspase-9 was changed by treatment with HDAC inhibitors, suggesting the possibility that HDAC inhibitor-induced apoptosis was not mediated by the mitochondrial cell death pathway. On the other hand, immunoblot assay confirmed increased expression of caspase-8 in both lines, and elevation of p21 but not p27 protein in U251-MG cells following HDAC inhibitor treatment. Taken together, the HDAC inhibitors, N-butyric acid and trichostatin A, induce caspase-8- but not caspase-9-dependent apoptosis with or without p21-mediated G1 arrest in human malignant glioma cells.
 ...
PMID:Histone deacetylase inhibitors, N-butyric acid and trichostatin A, induce caspase-8- but not caspase-9-dependent apoptosis in human malignant glioma cells. 1580 27

Ellipticine, a cytotoxic plant alkaloid, is known to inhibit topoisomerase II. Here, we first report the molecular mechanism of ellipticine's apoptotic action in human breast MCF-7 cancer cells. Treatment of cells with ellipticine resulted in inhibition of growth, and G2/M phase arrest of the cell cycle. This effect was associated with a marked increase in the protein expression of p53 and, p21/WAF1 and KIP1/p27, but not of WAF1/p21. Ellipticine treatment increased the expression of Fas/APO-1 and its ligands, mFas ligand and sFas ligand, and subsequent activation of caspase-8. The mitochondrial apoptotic pathway amplified the Fas/Fas ligand death receptor pathway by Bid interaction. This effect was found to result in a significant increase in activation of caspase-9. Taken together, we have concluded that the molecular mechanisms during ellipticine-mediated growth inhibition and induction of apoptosis in MCF-7 cells were due to (1) cell cycle arrest and induction of apoptosis, (2) induction of p53 and KIP1/p27 expression, (3) triggering of Fas/Fas ligand pathway, (4) disruption of mitochondrial function, and (5) the apoptotic signaling was amplified by cross-talk between Fas death receptor and mitochondrial apoptotic pathway.
 ...
PMID:The mechanism of ellipticine-induced apoptosis and cell cycle arrest in human breast MCF-7 cancer cells. 1589 64

The aim of the current study was to evaluate the protein expression involved in the progression from dysplasia to invasive esophageal squamous cell carcinomas and to analyze the prognostic value of markers. Immunohistochemistry was performed for cell cycle regulators [p53, p21, p27, p16, cyclin D1, Rb], apoptosis-related proteins [Fas, Fas-L, FADD, TRAIL, DR4, DR5, caspase-8, caspase-3, bcl-2, Bax], tumor suppressor proteins [beta-catenin, E-cadherin, FHIT, Smad 4, VHL, PTEN, KAI-1], and oncoproteins [c-myc, COX-2, EGFR]. Caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR revealed significant differences between dysplasia and their corresponding invasive cancer portion in 25 cases. In a total of 118 cases of invasive cancer, proteins with frequent (> or = 60% of the cases) alterations were p53 (overexpression in 64% of SCCs), p27 (loss in 91%), p16 (loss in 81%), and FHIT (loss in 75%). Early clinical stage and bcl-2 immunopositivity were related to the survival rate of patients. In conclusion, caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR may be involved in the progression from dysplasia to invasive esophageal SCCs. Clinical stage and bcl-2 are independent prognostic factors throughout the multivariate analysis.
 ...
PMID:Differential protein expression between esophageal squamous cell carcinoma and dysplasia, and prognostic significance of protein markers. 1613 47


1 2 3 4 5 6 7 Next >>