Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) is highly resistant to chemotherapy, leading to a poor prognosis of advanced disease. Inhibitors of histone deacetylase (HDACi) induce re-differentiation in tumor cells and thereby re-establish sensitivity towards apoptotic stimuli. HDACi are entering the clinical stage of tumor treatment, and several substances are currently being tested in clinical trials to prove their efficacy in the treatment of leukemias and solid tumors. In this study, we investigated the impact of the HDACi valproic acid (VA) on TRAIL- and CD95-mediated apoptosis in hepatoma cells, as well as its sensitizing effect on a chemotherapeutic agent. Treatment of HepG2 cells with VA increased sensitivity to CD95-mediated apoptosis (4% apoptosis vs. 42%), and treatment with epirubicin (74% vs. 90% viability). Caspase-3 activity was significantly enhanced in cells treated with VA plus anti-CD95 antibodies compared to cells treated with antibodies alone. In parallel, VA strongly augmented the effect of TNF-related apoptosis-inducing ligand (TRAIL or Apo2 ligand) on HepG2 cells (10% vs. 58% apoptosis). VA induced down-regulation of cellular FLICE-inhibitory protein (c-FLIP/CASH, also known as Casper/iFLICE/FLAME-1/CLARP/MRIT/usurpin), providing a possible molecular mechanism underlying the increased sensitivity towards cell death-mediated apoptosis. HDAC inhibitors are a promising class for the treatment of leukemias. In addition, among other class members, VA deserves further evaluation as a treatment option for patients with advanced HCC.
 ...
PMID:Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95- and TRAIL receptor-mediated apoptosis and chemotherapy. 1632 60

In general, oral squamous cell carcinoma (OSCC) cells are relatively resistant to Fas-mediated apoptosis during in vitro culture. Here, we studied the role of survival/apoptosis associated phosphatidylinositol 3-kinase (PI 3-K)/Akt in this process. We found that both PI 3-K inhibitors, wortmannin and LY294002, markedly suppressed the phosphorylation of Akt and accelerated Fas-mediated apoptosis in OSCC cells. It was found that caspase-3 and -8 inhibitors reduced the accelerative effect of PI 3-K inhibitor on Fas-mediated apoptosis in OSCC cells, but not caspase-9 inhibitor. Although PI 3-K inhibitors did not affect the Fas expression of OSCC cells, cellular FLICE-inhibitory protein (c-FLIP) levels were markedly reduced by PI 3-K inhibitor treatment. Moreover, antisense oligonucleotide to c-FLIP confirmed that the down-regulation of c-FLIP enhanced the sensitization to Fas-mediated apoptosis in OSCC cells. These results suggest that PI 3-K/Akt signaling pathway may, in part, regulate Fas-mediated apoptosis in OSCC cells through c-FLIP expression.
 ...
PMID:Enhancement of susceptibility to Fas-mediated apoptosis in oral squamous cell carcinoma cells by phosphatidylinositol 3-kinase inhibitor. 1652 14

The pathway of interferon-gamma (IFN-gamma)-induced suppression in tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS) was investigated. rTRAIL triggered FLS apoptosis in a type II cell death manner, whereas IFN-gamma pretreatment significantly inhibited TRAIL-mediated apoptosis. As disruption of mitochondrial transmembrane potential (DeltaPsim), Leu-Glu-His-Asp ase (IETD ase) activity, and the appearance of hypodiploid DNA + cells were markedly suppressed in IFN-gamma-treated FLS in response to TRAIL, IFN-gamma-induced suppression was supposed to achieve at upstream of caspase-8. IFN-gamma rapidly phosphorylated signal transducers and activators of transcription 1 (STAT1), STAT3, and STAT6 as well as ERK, whereas enhanced neither phosphorylation of Akt nor nuclear translocation of nuclear factor kappaB (NF-kappaB) p65. Janus kinase (JAK)-induced phosphorylation of STAT1/3/6, which acts at translational regulation, seemed to be crucial because chemical inhibition of JAK as well as cycloheximide (CHX) abolished both the phosphorylation of STAT1/3/6 and the IFN-gamma-induced inhibitory effect. Although ERK was phosphorylated through IFN-gamma, chemical inhibition of ERK by PD98059 did not abolish the IFN-gamma-induced inhibitory effect. The authors tried to determine the responsible molecules; however, expression of TRAIL receptors; pro-caspase-3/-8/-9; Fas-associated death domain protein (FADD); tumor necrosis factor receptor 1-associated death domain protein (TRADD); silencer of death domain (SODD); FLICE inhibitory protein (FLIP); and Bcl-2, Bcl-xL, and Bax in FLS was not modulated by IFN-gamma. Although the authors have not yet clarified the precise mechanism, these data suggest that IFN-gamma/JAK/STAT pathway, which is supposed to be activated in inflammatory rheumatoid arthritis (RA) synovial tissues, contributes to form apoptosis resistance phenotype of the cells in situ, leading to a marked increase in cellularity of synovial cells.
 ...
PMID:Significant inhibition of TRAIL-mediated fibroblast-like synovial cell apoptosis by IFN-gamma through JAK/STAT pathway by translational regulation. 1658 46

We have previously shown that hepatitis C virus (HCV) core protein modulates multiple cellular processes, including those that inhibit tumor necrosis factor alpha (TNF-alpha)-mediated apoptosis. In this study, we have investigated the signaling mechanism for inhibition of TNF-alpha-mediated apoptosis in human hepatoma (HepG2) cells expressing core protein alone or in context with other HCV proteins. Activation of caspase-3 and the cleavage of DNA repair enzyme poly(ADP-ribose) polymerase were inhibited upon TNF-alpha exposure in HCV core protein-expressing HepG2 cells. In vivo protein-protein interaction studies displayed an association between TNF receptor 1 (TNFR1) and TNFR1-associated death domain protein (TRADD), suggesting that the core protein does not perturb this interaction. A coimmunoprecipitation assay also suggested that HCV core protein does not interfere with the TRADD-Fas-associated death domain protein (FADD)-procaspase-8 interaction. Further studies indicated that HCV core protein expression inhibits caspase-8 activation by sustaining the expression of cellular FLICE (FADD-like interleukin-1beta-converting enzyme)-like inhibitory protein (c-FLIP). Similar observations were also noted upon expression of core protein in context to other HCV proteins expressed from HCV full-length plasmid DNA or a replicon. A decrease in endogenous c-FLIP by specific small interfering RNA induced TNF-alpha-mediated apoptotic cell death and caspase-8 activation. Taken together, our results suggested that the TNF-alpha-induced apoptotic pathway is inhibited by a sustained c-FLIP expression associated with the expression of HCV core protein, which may play a role in HCV-mediated pathogenesis.
 ...
PMID:Hepatitis C virus core protein inhibits tumor necrosis factor alpha-mediated apoptosis by a protective effect involving cellular FLICE inhibitory protein. 1661 96

Inadequate apoptosis may contribute to the synovial hyperplasia associated with rheumatoid arthritis (RA). The Fas-associated death domain protein (FADD)-like interleukin (IL)-1beta-converting enzyme (FLICE)-inhibitory protein (FLIP), which is an apoptotic inhibitor, has been implicated in the resistance to Fas-mediated apoptosis of synoviocytes. This study investigated whether hydroxychloroquine (HCQ), an anti-rheumatic drug, induces the apoptosis of rheumatoid synoviocytes, and modulates the expression of FLIP. Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of RA patients, and were cultured with various concentrations of HCQ in the presence or absence of the IgM anti-Fas monoclonal antibodies (mAb) (CH11). Treatment with HCQ, ranging from 1 to 100 microM, induced the apoptosis of FLS in a dose- and time-dependent manner. The increase in synoviocytes apoptosis by HCQ was associated with caspase-3 activation. A combined treatment of HCQ and anti-Fas mAb increased FLS apoptosis and caspase-3 activity synergistically, compared with either anti-Fas mAb or HCQ alone. The Fas expression level in the FLS was not increased by the HCQ treatment, while the FLIP mRNA and protein levels were decreased rapidly by the HCQ treatment. Moreover, time kinetics analysis revealed that the decreased expression of FLIP by HCQ preceded the apoptotic event that was triggered by HCQ plus anti-Fas mAb. Taken together, HCQ increases the apoptosis of rheumatoid synoviocytes by activating caspase-3, and also sensitizes rheumatoid synoviocytes to Fas-mediated apoptosis. Our data suggest that HCQ may exert its anti-rheumatic effect in rheumatoid joints through these mechanisms.
 ...
PMID:Hydroxychloroquine potentiates Fas-mediated apoptosis of rheumatoid synoviocytes. 1673 20

Induction of apoptosis by the death ligand TRAIL might be a promising therapeutic approach in cancer therapy. However, since not all tumor cells are sensitive to TRAIL, there is a need for the development of strategies to overcome TRAIL-resistance. The results of the present study show that the anti-diabetic drug troglitazone sensitizes human glioma and neuroblastoma cells to TRAIL-induced apoptosis. This process is accompanied by a substantial increase of active caspase 8 and active caspase 3, but it is independent of troglitazone's effects on the nuclear receptor PPAR-gamma. Troglitazone induces a pronounced reduction in protein expression levels of the anti-apoptotic FLICE-inhibitory protein (FLIP) without affecting FLIP mRNA levels. Further, protein and mRNA expression levels of the anti-apoptotic protein Survivin significantly decrease upon treatment with troglitazone. Moreover, sensitization to TRAIL is partly accompanied by an up-regulation of the TRAIL receptor, TRAIL-R2. A combined treatment with troglitazone and TRAIL might be a promising experimental therapy because troglitazone sensitizes tumor cells to TRAIL-induced apoptosis via various mechanisms, thereby minimizing the risk of acquired tumor cell resistance.
 ...
PMID:Troglitazone sensitizes tumor cells to TRAIL-induced apoptosis via down-regulation of FLIP and Survivin. 1682 Sep 65

Tumor necrosis factor-alpha (TNF-alpha) is elevated in the serum as a result of aging and it promotes pro-apoptotic signaling upon binding to the type I TNF receptor. It is not known if activation of this apoptotic pathway contributes to the well-documented age-associated decline in muscle mass (i.e. sarcopenia). We tested the hypothesis that skeletal muscles from aged rodents would exhibit elevations in markers involved in the extrinsic apoptotic pathway when compared to muscles from young adult rodents, thereby contributing to an increased incidence of nuclear apoptosis in these muscles. The plantaris (fast) and soleus (slow) muscles were studied in young adult (5-7 mo, n=8) and aged (33 mo, n=8) Fischer(344) x Brown Norway rats. Muscles from aged rats were significantly smaller while exhibiting a greater incidence of apoptosis. Furthermore, muscles from aged rats had higher type I TNF receptor and Fas associated death domain protein (FADD) mRNA, protein contents for FADD, BCL-2 Interacting Domain (Bid), FLICE-inhibitory protein (FLIP), and enzymatic activities of caspase-8 and caspase-3 than muscles from young adult rats. Significant correlations were observed in the plantaris muscle between caspase activity and muscle weight and the apoptotic index, while similar relationships were not found in the soleus. These data demonstrate that pro-apoptotic signaling downstream of the TNF receptor is active in aged muscles. Furthermore, our data extend the previous demonstration that type II fibers are preferentially affected by aging and support the hypothesis that type II fiber containing skeletal muscles may be more susceptible to muscle mass loses via the extrinsic apoptotic pathway.
 ...
PMID:Death receptor-associated pro-apoptotic signaling in aged skeletal muscle. 1705 37

Stimulation of Fas-mediated apoptosis has been promoted as a potential therapy for many cancers, including cholangiocarcinoma. We have previously reported that Fas-resistant, but not Fas-sensitive, cholangiocarcinoma cells are tumorigenic in nude mice. The present studies sought to identify molecular targets that promote Fas-mediated apoptosis in cholangiocarcinoma. We found that Fas-resistant cholangiocarcinoma cells exhibited increased constitutive phosphorylation of AKT compared with Fas-sensitive cells. Increased phosphorylation of AKT was also demonstrated in human cholangiocarcinoma tumors and was evident in a mouse xenograft cholangiocarcinoma model. Furthermore, we found that 3,3'-diindolylmethane (DIM), a vegetable autolysis product, promoted Fas-mediated apoptosis of cholangiocarcinoma cells. DIM inhibited phosphorylation of AKT and activation of FLICE-like-inhibitory-protein (FLIP). Inhibition of phosphatidylinositol 3-kinase/AKT decreased FLIP activation and promoted Fas-mediated apoptosis. By contrast, adenovirus-mediated constitutively activated AKT protected cholangiocarcinoma cells from Fas-mediated apoptosis. Decreased activation of extracellular signal-regulated kinase and nuclear factor-kappaB and increased activation of caspase-3, -8, and -9 were associated with inhibition of AKT and FLIP. These results support AKT and FLIP as potential molecular targets and DIM as a potent compound for cholangiocarcinoma intervention.
 ...
PMID:Fas-mediated apoptosis in cholangiocarcinoma cells is enhanced by 3,3'-diindolylmethane through inhibition of AKT signaling and FLICE-like inhibitory protein. 1707 4

The administration of tumor necrosis factor-alpha (TNF-alpha) or the anti-Fas antibody (Jo-2) to mice causes acute liver failure, which is lethal within hours as a result of the induction of apoptosis in hepatocytes. It was recently reported that nonobese diabetic (NOD) mice are less sensitive to TNF-alpha/D-galactosamine (GalN)-induced liver failure than C57BL/6J (B6) mice, whereas both NOD and B6 mice were sensitive to the lethal effect of Jo-2. In the present study, we investigated the differences between the apoptotic liver cell death induced by TNF-alpha/GalN and that induced by Jo-2. B6, NOD, and Jcl-Imperial Cancer Research (ICR) mice were injected intravenously with TNF-alpha/GalN or Jo-2. ICR mice were less sensitive to TNF-alpha/GalN-induced liver failure than NOD and B6 mice (P<0.0001). In contrast, ICR mice were more sensitive to Jo-2-induced liver failure than B6 mice (P=0.0003). The liver caspase-3, -8 activity, serum transaminase levels, and the number of apoptotic liver nuclei all decreased in ICR in comparison to B6 mice treated with TNF-alpha/GalN. The mRNA expression of TNFR-associated death domain, Fas associated protein with death domain, and Bcl family and nuclear factor-kappaB activation induced by TNF-alpha/GalN were similar in both mice. Interestingly, the short form of cellular FLICE/caspase-8-inhibitory protein (c-FLIP(S)) was constitutively upregulated in ICR mice. In conclusion, these results suggest that ICR mice have an intrinsic resistance to TNF-alpha-induced hepatocyte apoptosis, and that c-FLIP(S) may play a role in TNF-alpha/GalN-induced liver failure, but not in Fas-induced liver failure.
 ...
PMID:Intrinsic resistance to TNF-alpha-induced hepatocyte apoptosis in ICR mice correlates with expression of a short form of c-FLIP. 1737 87

In general, oral squamous cell carcinoma (OSCC) cells are relatively resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis during culture in vitro. Here, we studied the role of phosphatidylinositol 3-kinase (PI 3-K)/Akt in survival and apoptosis of these cells. The PI 3-K inhibitors wortmannin and LY294002 markedly suppressed phosphorylation of Akt and accelerated TRAIL-mediated apoptosis in OSCC cells. Addition of TRAIL to PI 3-K inhibitor-treated cells resulted in caspase-8 activation and loss of mitochondrial membrane potential. Furthermore, inhibitors of caspase-3, -8 and -9 reduced the accelerative effect of PI 3-K inhibitors on TRAIL-mediated apoptosis. These results suggest that the pro-apoptotic effect of PI 3-K inhibitors on TRAIL-mediated apoptosis may contribute to both the extrinsic and intrinsic pathways. Although PI 3-K inhibitors did not affect expression of the TRAIL receptors DR4 and DR5, we observed a marked reduction in expression of cellular FLICE-inhibitory protein (c-FLIP), Bcl-2, cellular inhibitor of apoptosis protein-1 (cIAP-1) and X-linked IAP (XIAP), whereas Bax was up-regulated and no significant difference was observed in expression of Bcl-xL, Bak or cIAP-2. Therefore, the PI 3-K/Akt signaling pathway provides partial regulation of TRAIL-mediated apoptosis in OSCC cells via modulation of c-FLIP, Bcl-2, Bax, cIAP-1 and XIAP expression. These results suggest that PI 3-K inhibitors may represent a novel strategy for overcoming resistance to TRAIL-mediated apoptosis in OSCC cells.
 ...
PMID:Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors. 1739 18


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>