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

Our aim was to study the anticancer effect of the novel immunomodulator FTY720 in vitro and in vivo by investigation of cell cycle entry, cell cycle regulation, cell survival and apoptosis pathways. Three hepatoma cell lines with different p53 statuses (HepG2, Huh-7 and Hep3B) and one non-tumorigenic immortalized liver cell line (MIHA) were used for an in vitro study. The in vivo effects of FTY720 were evaluated in a nude mouse tumor model. Cell cycle distribution and cell cycle regulator proteins p27(Kip1) and cyclin D1, together with the PI3-K/Akt pathway, mitogen-activated protein kinases and cleaved caspase-3 and caspase-9, were evaluated. FTY720 selectively induced cell apoptosis in hepatoma cell lines with overexpression of cleaved caspase-3 and caspase-9, but the same phenomena were not found in MIHA cells. FTY720 induced Akt dephosphorylation at Ser473 mediated by phosphoinositide 3-kinase (PI3-K) inhibition. Dephosphorylation led to down-regulation of p42/p44 and dephosphorylation of Forkhead transcription factor and GSK-3beta and, subsequently, up-regulation of p27(Kip1) and down-regulation of cyclin D1. In our in vivo model FTY720 induced apoptosis of tumor cells by down-regulation of the Akt pathway. FTY720 suppressed tumor growth without notable side-effects in normal liver. In conclusion, FTY720 is a novel anticancer agent that induces apoptosis of hepatoma cell lines both in vitro and in vivo through PI3-K-mediated Akt dephosphorylation in a p53-independent manner.
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PMID:FTY720 induces apoptosis of human hepatoma cell lines through PI3-K-mediated Akt dephosphorylation. 1529 71

The N-methyl-d-aspartate (NMDA) receptor 2B-selective antagonist ifenprodil induced morphological changes which were characterized by cell shrinkage, nuclear condensation or fragmentation, and internucleosomal DNA fragmentation in rat cultured cortical cells. Ifenprodil increased the apoptotic cell death in a dose-dependent manner (0.5-10 microM). In addition, the protein synthesis inhibitor cycloheximide completely blocked ifenprodil-induced apoptotic cell death. The selective inhibitors of glycogen synthase kinase-3 (GSK-3) prevented the ifenprodil-induced apoptosis. Moreover, activation of caspase-3 was accompanied by cell death induced by ifenprodil in a dose-dependent manner. The ifenprodil-induced apoptosis was prevented by a caspase-3 inhibitor. These results suggested that activation of GSK-3 involves in the apoptosis induced by blocking of trophic effect of NMDA receptor consisting of NR2B subunit in rat cortical neurons.
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PMID:NMDA receptor 2B-selective antagonist ifenprodil-induced apoptosis was prevented by glycogen synthase kinase-3 inhibitors in cultured rat cortical neurons. 1531 3

Insulin-like growth factor-I (IGF-I) protects neurons of the peripheral nervous system from apoptosis, but the underlying signaling pathways are not well understood. We studied IGF-I mediated signaling in embryonic dorsal root ganglia (DRG) neurons. DRG neurons express IGF-I receptors (IGF-IR), and IGF-I activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. High glucose exposure induces apoptosis, which is inhibited by IGF-I through the PI3K/Akt pathway. IGF-I stimulation of the PI3K/Akt pathway phosphorylates three known Akt effectors: the survival transcription factor cyclic AMP response element binding protein (CREB) and the pro-apoptotic effector proteins glycogen synthase kinase-3beta (GSK-3beta) and forkhead (FKHR). IGF-I regulates survival at the nuclear level through accumulation of phospho-Akt in DRG neuronal nuclei, increased CREB-mediated transcription, and nuclear exclusion of FKHR. High glucose increases expression of the pro-apoptotic Bcl protein Bim (a transcriptional target of FKHR). However, IGF-I does not regulate Bim or anti-apoptotic Bcl-xL protein expression levels, which suggests that IGF-I neuroprotection is not through regulation of their expression. High glucose also induces loss of the initiator caspase-9 and increases caspase-3 cleavage, effects blocked by IGF-I. These data suggest that IGF-I prevents apoptosis in DRG neurons by regulating PI3K/Akt pathway effectors, including GSK-3beta, CREB, and FKHR, and by blocking caspase activation.
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PMID:Phosphatidylinositol 3-kinase and Akt effectors mediate insulin-like growth factor-I neuroprotection in dorsal root ganglia neurons. 1531 68

Studies to investigate signal transduction pathways that support viability and prevent apoptosis of chronic lymphocytic leukemia cells (CLL) were initiated as a result of microarray cDNA analyses which revealed expression of genes whose products regulate cell cycle progression. Immunoblots revealed translation of several genes including caspases, cyclin D1, and the PI3-kinase dependent, survival kinase, Akt. Akt was found to be activated. Inhibition of PI3-kinase with specific inhibitor, LY294002, led to the induction of apoptosis that was caspase 8 dependent, but independent of Akt as LY294002 did not depress a high basal level of Akt activity found in CLL cells. Phosphorylation of Akt was maintained, enzymatic activity undiminished, and phosphorylation of substrates sustained. Caspases, however were activated, PARP cleaved and DNA fragmented. Caspase inhibitors revealed that initiator caspase 8 was required for classic apoptosis when PI3-kinase was inhibited, and specific activity assays demonstrated its early activation. GSK-3beta a kinase regulated via PI3-kinase dependent, down-stream kinases, was responsible for regulating cyclin D1 levels in CLL cells, but neither GSK-3beta nor calpain was responsible for induction of apoptosis, or activation of executioner caspase 3, following LY294002 treatment. PI3-kinase mediated protection against caspase activation in CLL B-cells therefore is not mediated through classic Akt survival pathways. The data further support the hypothesis that signal transducing, membrane associated receptors triggered by extrinsic factors, maintain CLL leukemic B-cell survival in vivo by preventing caspase activation.
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PMID:PI3-kinase regulates survival of chronic lymphocytic leukemia B-cells by preventing caspase 8 activation. 1537 Feb 2

Fucoidan, a sulfated polysaccharide in brown seaweed, was found to inhibit proliferation and induce apoptosis in human lymphoma HS-Sultan cell lines. Fucoidan-induced apoptosis was accompanied by the activation of caspase-3 and was partially prevented by pretreatment with a pan-caspase inhibitor, z-VAD-FMK. The mitochondrial potential in HS-Sultan cells was decreased 24 hr after treatment with fucoidan, indicating that fucoidan induced apoptosis through a mitochondrial pathway. When HS-Sultan was treated with 100 microg/mL fucoidan for 24 hr, phosphorylation of ERK and GSK markedly decreased. In contrast, phosphorylation of p38 and Akt was not altered by treatment with fucoidan. L-selectin and P-selectin are known to be receptors of fucoidan; however, as HS-Sultan does not express either of these selectins, it is unlikely that fucoidan induced apoptosis through them in HS-Sultan. The neutralizing antibody, Dreg56, against human L-selectin did not prevent the inhibitory effect of fucoidan on the proliferation of IM9 and MOLT4 cells, both of which express L-selectin; thus it is possible fucoidan induced apoptosis though different receptors. These results demonstrate that fucoidan has direct anti-cancer effects on human HS-Sultan cells through caspase and ERK pathways.
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PMID:Fucoidan induces apoptosis of human HS-sultan cells accompanied by activation of caspase-3 and down-regulation of ERK pathways. 1560 79

The effects of diallyl disulfide (DADS), a garlic-derived compound, on the viability of neuronal cells and cell signals, including phosphatidylinositol 3-kinase (PI3K)/Akt, glycogen synthase kinase-3 (GSK-3), cytochrome c, caspase-3, and poly(ADP-ribose) polymerase (PARP), were investigated in PC12 cells neuronally differentiated by nerve growth factor. To evaluate the toxicity of DADS itself, nPC12 cells were treated with several concentrations of DADS, and 3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue stain revealed that the viability was not affected by low concentration of DADS, up to 20 microM, but it was decreased at higher than this concentration. The levels of free radicals and membrane lipid peroxidation were significantly increased in nPC12 cells when treated with more than 50 microM DADS, and treatment of PC12 cells with 100 microM DADS killed the cells by inhibiting PI3K/Akt and by promoting activation of GSK-3 and caspase-3, release of cytochrome c, and cleavage of PARP. To evaluate the protective effects of low concentration of DADS on oxidative stress-injured nPC12 cells, the viability of the cells (pretreated with DADS for 2 h vs. not pretreated) was evaluated 24 h after exposure to 100 microM H2O2 for 30 min. Compared to the cells treated with 100 microM H2O2 only, pretreatment of the cells with 20 microM DADS before exposure to 100 microM H2O2 increased the viability and induced activation of PI3K and Akt, inactivation of GSK-3, and inhibition of cytochrome c release, caspase-3 activation, and PARP cleavage. These results indicate that low concentration of DADS has neuroprotective effects by activating PI3K/Akt and by inhibiting GSK-3 activation, cytochrome c release, caspase-3 activation, and PARP cleavage, whereas high concentration is rather cytotoxic. Therefore, some specific optimum concentration of DADS may be a new potential therapeutic strategy for oxidative stress injured in vitro model of neurodegenerative diseases.
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PMID:Protective effect of diallyl disulfide on oxidative stress-injured neuronally differentiated PC12 cells. 1571 Feb 34

Point mutations such as G93A and A4V in the human Cu/Zn-superoxide dismutase gene (hSOD1) cause familial amyotrophic lateral sclerosis (fALS). In spite of several theories to explain the pathogenic mechanisms, the mechanism remains largely unclear. Increased activity of glycogen synthase kinase-3 (GSK-3) has recently been emphasized as an important pathogenic mechanism of neurodegenerative diseases, including Alzheimer's disease and ALS. To investigate the effects of G93A or A4V mutations on the phosphatidylinositol-3-kinase (PI3-K)/Akt and GSK-3 pathway as well as the caspase-3 pathway, VSC4.1 motoneuron cells were transfected with G93A- or A4V-mutant types of hSOD1 (G93A and A4V cells, respectively) and, 24 h after neuronal differentiation, their viability and intracellular signals, including PI3-K/Akt, GSK-3, heat shock transcription factor-1 (HSTF-1), cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those of wild type (wild cells). Furthermore, to elucidate the role of the GSK-3beta-mediated cell death mechanism, alterations of viability and intracellular signals in those mutant motoneurons were investigated after treating the cells with GSK-3beta inhibitor. Compared with wild cells, viability was greatly reduced in the G93A and A4V cells. However, the treatment of G93A and A4V cells with GSK-3beta inhibitor increased their viability by activating HSTF-1 and by reducing cytochrome c release, caspase-3 activation and PARP cleavage. However, the treatment did not affect the expression of PI3-K/Akt and GSK-3beta. These results suggest that the G93A or A4V mutations inhibit PI3-K/Akt and activate GSK-3beta and caspase-3, thus becoming vulnerable to oxidative stress, and that the GSK-3beta-mediated cell death mechanism is important in G93A and A4V cell death.
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PMID:Role of GSK-3beta activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene. 1604 83

The PI3-kinase/Akt pathway promotes cell survival in many different cell types including intestinal epithelial cells. Increased AKT activation in polyamine depleted intestinal epithelial cells correlated well with the decrease in TNF-alpha-induced apoptosis. Increased Akt activation and GSK3beta (Ser 9) phosphorylation without significant effect on Bad (Ser136) phosphorylation indicate that Akt-mediated protection is independent of Bad phosphorylation but may depend on GSK3beta. Pretreatment of polyamine-depleted cells with LY294002 increased caspase-9 and caspase-3 activation and decreased basal levels of GSK-3beta phosphorylation. Inhibition of GSK3beta activity using AR-A014418 or lithium chloride or siRNA-mediated downregulation of its expression had no effect on apoptosis. Inhibition of PI3-kinase and over-expression of dominant negative Akt (DN-AKT), significantly increased apoptosis in polyamine depleted cells. DN-Akt expression reversed the protective effect of polyamine depletion on apoptosis. DN-Akt, as well as the PI3-kinase inhibitors, prevented Akt activation and subsequent translocation of NF-kappaB to the nucleus. Constitutively active Akt (CA-AKT) expression increased resistance to TNF-alpha-induced apoptosis. Constitutively active-Akt expression increased nuclear staining of NF-kappaB. Moreover, polyamine depletion of DN-Akt cells prevented basal and TNF-alpha-induced IkappaBalpha phosphorylation. Prevention of NF-kappaB activation in DN-IkappaBalpha-transfected cells increased apoptosis in control cells and restored it in polyamine-depleted cells to control levels. These data indicate that Akt regulates the mitochondrial pathway, preventing activation of caspase-9 and thereby caspase-3 via NF-kappaB and these effects are independent of GSK-3beta activity.
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PMID:Decreased apoptosis in polyamine depleted IEC-6 cells depends on Akt-mediated NF-kappaB activation but not GSK3beta activity. 1613 67

Recent data suggest that anesthetic drugs cause neurodegeneration during development. Ketamine is frequently used in infants and toddlers for elective surgeries. The purpose of this study is to determine whether glycogen synthase kinase-3 (GSK-3) is involved in ketamine-induced apoptosis. Ketamine increased apoptotic cell death with morphological changes which were characterized by cell shrinkage, nuclear condensation or fragmentation. In addition, insulin growth factor-1 completely blocked the ketamine-induced apoptotic cell death. Ketamine decreased Akt phosphorylation. GSK-3 is known as a downstream target of Akt. The selective inhibitors of GSK-3 prevented the ketamine-induced apoptosis. Moreover, caspase-3 activation was accompanied by the ketamine-induced cell death and inhibited by the GSK-3 inhibitors. These results suggest that activation of GSK-3 is involved in ketamine-induced apoptosis in rat cortical neurons.
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PMID:Ketamine-induced apoptosis in cultured rat cortical neurons. 1630 66

Hypertrophic cardiomyopathy (HCM) is the most common form of sudden death in young competitive athletes. However, exercise has also been shown to be beneficial in the setting of other cardiac diseases. We examined the ability of voluntary exercise to prevent or reverse the phenotypes of a murine model of HCM harboring a mutant myosin heavy chain (MyHC). No differences in voluntary cage wheel performance between nontransgenic (NTG) and HCM male mice were seen. Exercise prevented fibrosis, myocyte disarray, and induction of "hypertrophic" markers including NFAT activity when initiated before established HCM pathology. If initiated in older HCM animals with documented disease, exercise reversed myocyte disarray (but not fibrosis) and "hypertrophic" marker induction. In addition, exercise returned the increased levels of phosphorylated GSK-3beta to those of NTG and decreased levels of phosphorylated CREB in HCM mice to normal levels. Exercise in HCM mice also favorably impacted components of the apoptotic signaling pathway, including Bcl-2 (an inhibitor of apoptosis) and procaspase-9 (an effector of apoptosis) expression, and caspase-3 activity. Remarkably, there were no differences in mortality between exercised NTG and HCM mice. Thus, not only was exercise not harmful but also it was able to prevent and even reverse established cardiac disease phenotypes in this HCM model.
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PMID:Exercise can prevent and reverse the severity of hypertrophic cardiomyopathy. 1651 74


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