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)

In this study, we first demonstrated that the widely used oral antifungal drug, ketoconazole (KT), can induce apoptosis in various type of human cancer cells and in a primary culture of rat liver cells. We further investigated the molecular mechanisms of KT-induced apoptosis. It was found that KT induced nuclear accumulation of p53 protein in a dose- and time-dependent manner. The level of p53 protein was elevated approximately three times as much in treated cells 24 h after KT (5 microM) exposure as in cells receiving mock treatment. We found that cells containing wild-type p53 (COLO 205 and Hep G2) were more sensitive to KT exposure. The bax protein was induced and the bcl-2 protein was inhibited by KT in cells containing wild-type p53 (Hep G2, COLO 205) but not in cells without p53 (Hep 3B). The caspase-3 was activated 24 h after KT treatment. The Poly-(ADP ribose) polymerase (PARP) and the lamin A degradation was induced by KT, which promoted nuclear membrane disassembly and eventually caused apoptosis. Our results also indicated that none of the PKC gene family was involved in KT-induced apoptosis.
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PMID:Ketoconazole-induced apoptosis through P53-dependent pathway in human colorectal and hepatocellular carcinoma cell lines. 987 98

Solid tumors usually have regions of hypoxia and glucose deprivation. Human colon carcinoma HT-29 cells show an apoptosis-resistant phenotype in response to microenvironmental stresses. In this study, we isolated a novel mutant of HT-29, designated as HA511, that showed a high apoptotic response to hypoxia, glucose deprivation and treatment with the chemical stressors tunicamycin and glucosamine. The mutant HA511 cells exhibited nuclear condensation and fragmentation and activation of CPP32 (caspase-3) protease under the stress conditions, while the parental HT-29 cells did not. We found that apoptosis occurred in HA511 cells after prolonged cell cycle arrest at the G1 phase, while in the parental cells a progression to S phase occurred after the G1 arrest. Upon exposure to an anti-Fas antibody, HA511 cells underwent apoptosis, whereas the parental cells proliferated without substantial cell death. Furthermore, HA511 cells were preferentially hypersensitive to cisplatin. We found no alteration in expression of GRP78, anti-apoptotic protein Bcl-XL, or p53, of which the gene was mutated in HT-29 cells. The mutant HA511 cells could provide useful information on the mechanism of apoptosis of solid tumors.
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PMID:A novel mutant from apoptosis-resistant colon cancer HT-29 cells showing hyper-apoptotic response to hypoxia, low glucose and cisplatin. 991 86

Although p53 has been shown to directly activate transcriptional bax gene and to inhibit expression of bcl-2 gene during radiation-induced apoptosis, it is poorly understood how the Bcl-2 family changes in p53-deficient cells during radiation-induced apoptosis. The present work describes the effect of X-irradiation on the apoptosis of p53-deficient HL-60 cells as assessed by means of several methods. Apoptosis of HL-60 cells was induced by X-irradiation in a dose- and time-dependent manner. 18 h after 5 Gy irradiation, G2 cells underwent apoptosis, while 15 Gy X-irradiation induced the death of G1/S cells by 6 h. After X-irradiation, expression of Bcl-2 was elevated, while Bax expression was unchanged. We have isolated a clonal HL-60 variant following twice 5 Gy irradiation of HL-XR3 cells. These cells highly expressed Bcl-2 (about 2-fold), showed a reduced activation of caspase-3, and were not only more resistant to X-irradiation-induced apoptosis but also more radioresistant. These results suggest that HL-60 cells may resist apoptosis and radiation by increasing Bcl-2 expression, and that this elevated Bcl-2 expression might be one of the causes of the phenomenon, often seen clinically, that tumor cells gradually acquire radioresistance during fractionated radiation therapy.
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PMID:X-irradiation enhances the expression of Bcl-2 in HL-60 cells: the resulting effects on apoptosis and radiosensitivity. 991 21

The inhibitors of protein prenylation have been proposed for chemotherapy of tumors. Lovastatin, a 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitor, displays proapoptotic activity in tumor cells blocking the synthesis of isoprenoids compounds. To test whether HMG-CoA reductase inhibition can induce apoptosis in proliferating thyroid cells, we studied the effects of lovastatin in normal and neoplastic thyroid cells and in primary cultures from normal human thyroids. In an immortalized human thyroid cell line (TAD-2) and in neoplastic cells, lovastatin induced cell rounding within 24 h of treatment. After 48 h the cells were detached from the plate and underwent apoptosis, as evidenced by DNA fragmentation. Morphological changes and apoptosis did not occur in serum-starved quiescent TAD-2 cells or in primary cultures of normal thyrocytes. Mevalonate, the product of the HMG-CoA reductase enzymatic activity, and the protein synthesis inhibitor cycloheximide completely blocked the effects of lovastatin in a dose-dependent fashion. The geranylgeranyl transferase GGTI-298 inhibitor mimicked the effects of lovastatin on cell morphology and induced cell death, whereas the farnesyl transferase inhibitor FTI-277 was less effective to induce both cell rounding and apoptosis. Resistance to lovastatin-induced apoptosis by expression of the viral serpine CrmA and by the peptide inhibitor of caspases, Z-DEVD-fmk, demonstrated the involvement of CrmA-sensitive, caspase-3-like proteases. Inhibition of endogenous p53 activity did not affect the sensitivity of thyroid cells to lovastatin, demonstrating that this type of apoptosis is p53 independent. We conclude that lovastatin is a potent inducer of apoptosis in proliferating thyroid cells through inhibition of protein prenylation. This type of apoptosis requires protein synthesis, is CrmA sensitive and caspase-3-like protease dependent, and is independent from p53.
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PMID:Prenyltransferase inhibitors induce apoptosis in proliferating thyroid cells through a p53-independent CrmA-sensitive, and caspase-3-like protease-dependent mechanism. 992 96

The proteasome inhibitors lactacystin and AcLLNal induced p53-independent apoptosis in two human glioma cell lines, and the apoptosis was accompanied by up-regulation of immunoreactive wild-type p53, p21Waf1, Mdm2, and p27Kip1. Pretreatment with cycloheximide decreased the induction of cell death independently of p53 protein status, suggesting that the up-regulation of short-lived proteins is associated with proteasome inhibitor-induced apoptosis. Caspase-3-like proteases were activated in the proteasome inhibitor-mediated apoptosis, and the induction of cell death was inhibited more effectively in the presence of z-VAD.fmk than in the presence of Ac-DEVD.fmk, suggesting that caspases other than caspase-3 are involved. Nonetheless, there were no significant alterations in levels of immunoreactive Bcl-2, Bcl-X(L), Bax, Bad, and Bak, nor any evidence of cytochrome c release into cytosol and dissipation of delta(psi)m. Thus, the proteasome inhibitor-induced apoptosis is mediated by a mitochondria-independent mechanism, and the once activated caspase-3 does not cause the cytochrome c release and the delta(psi)m disruption.
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PMID:Proteasome inhibitors induce mitochondria-independent apoptosis in human glioma cells. 998 1

Reactive oxygen species (ROS) play an important role in cell death induced by many different stimuli. This study shows that hydrogen peroxide-induced apoptosis in T-cells did not require tyrosine kinase p561ck, phosphatase CD45, the CD95 receptor and its associated Caspase-8. H2O2-triggered cell death led to the induced cleavage and activation of Caspase-3. Hydrogen peroxide-treatment of T-cells resulted in the formation of mitochondrial permeability transition pores, a rapid decrease of the mitochondrial transmembrane potential delta psi(m) and the release of Cytochrome C. Inhibition of the mitochondrial permeability transition by bongkrekic acid (BA), or interference with the mitochondrial electron transport system by rotenone or menadione prevented the cytotoxic effect of H2O2. Antimycin A, a mitochondrial inhibitor that increases the release of mitochondrial ROS (MiROS), enhanced apoptosis. Overexpression of Bcl-2 and the viral anti-apoptotic proteins BHRF-1 and E1B 19K counteracted H2O2-induced apoptosis. Pharmacological and genetic inhibition of transcription factor NF-kappaB protected cells from hydrogen peroxide-elicited cell death. This detrimental effect of NF-kappaB mediating hydrogen peroxide-induced cell death presumably relies on the induced expression of death effector genes such as p53, which was NF-kappaB-dependently upregulated in the presence of H2O2.
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PMID:Hydrogen peroxide-induced apoptosis is CD95-independent, requires the release of mitochondria-derived reactive oxygen species and the activation of NF-kappaB. 998 25

The cyclin-dependent kinase inhibitor p21waf1/Cip1 is a downstream effector of the p53-dependent cell growth arrest. We report herein that p21 was cleaved by caspase-3/CPP32 at the site of DHVD112L during the DNA damage-induced apoptosis of cancer cells. The cleaved p21 fragment could no more arrest the cells in G1 phase nor suppress the cells undergoing apoptosis because it failed to bind to the proliferating cell nuclear antigen (PCNA) and lost its capability to localize in the nucleus. Thus, caspase-3-mediated cleavage and inactivation of p21 protein may convert cancer cells from growth arrest to undergoing apoptosis, leading to the acceleration of chemotherapy-induced apoptotic process in cancer cells.
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PMID:Caspase-mediated cleavage of p21Waf1/Cip1 converts cancer cells from growth arrest to undergoing apoptosis. 1002 18

The inflammatory mediator nitric oxide (NO*) promotes apoptotic cell death based on morphological evidence, accumulation of the tumor suppressor p53, caspase-3 activation, and DNA fragmentation in RAW 264.7 macrophages. Since nitrosothiols may actually be the predominant form of biologically active NO* in vivo, we used S-nitrosoglutathione (GSNO) to study activation of extracellular signal-regulated protein kinases1/2 (ERK1/2), c-Jun N-terminal kinases/stress-activated protein kinases (JNK1/2), and p38 kinases. Moreover, we determined the role of mitogen-activated protein kinase signaling in the apoptotic transducing ability of GSNO. ERK1/2 became activated in response to GSNO after 4 h and remained active for the next 20 h. Blocking the ERK1/2 pathway by the mitogen-activated protein kinase kinase inhibitor PD 98059 enhanced GSNO-elicited apoptosis. p38 was activated as well, but inhibition of p38 with SB 203580 left apoptosis unaltered. Activation of JNK1/2 by GSNO showed maximal kinase activities between 2 and 8 h. Attenuating JNK1/2 by antisense-depletion eliminated the pro-apoptotic action of low GSNO concentrations (250 microM), whereas apoptosis proceeded independently of JNK1/2 at higher doses of the NO donor (500 microM). Decreased apoptosis by JNK1/2 depletion prevented p53 accumulation after the addition of GSNO, which positions JNK1/2 upstream of the p53 response at low agonist concentrations. In line, JNK1/2 activation proceeded unaltered in p53-antisense transfected macrophages. However, with higher GSNO concentrations apoptotic transducing pathways, including p53 accumulation, were JNK1/2 unrelated. The regulation of mitogen-activated protein kinases by GSNO may help to define cell protective and destructive actions of reactive nitrogen species.
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PMID:Role of mitogen-activated protein kinases in S-nitrosoglutathione-induced macrophage apoptosis. 1002 20

This study was undertaken to investigate the molecular mechanisms underlying the neuroprotective actions of lithium against glutamate excitotoxicity with a focus on the role of proapoptotic and antiapoptotic genes. Long term, but not acute, treatment of cultured cerebellar granule cells with LiCl induces a concentration-dependent decrease in mRNA and protein levels of proapoptotic p53 and Bax; conversely, mRNA and protein levels of cytoprotective Bcl-2 are remarkably increased. The ratios of Bcl-2/Bax protein levels increase by approximately 5-fold after lithium treatment for 5-7 days. Exposure of cerebellar granule cells to glutamate induces a rapid increase in p53 and Bax mRNA and protein levels with no apparent effect on Bcl-2 expression. Pretreatment with LiCl for 7 days prevents glutamate-induced increase in p53 and Bax expression and maintains Bcl-2 in an elevated state. Glutamate exposure also triggers the release of cytochrome c from the mitochondria into the cytosol. Lithium pretreatment blocks glutamate-induced cytochrome c release and cleavage of lamin B1, a nuclear substrate for caspase-3. These results strongly suggest that lithium-induced Bcl-2 up-regulation and p53 and Bax down-regulation play a prominent role in neuroprotection against excitotoxicity. Our results further suggest that lithium, in addition to its use in the treatment of bipolar depressive illness, may have an expanded use in the intervention of neurodegeneration.
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PMID:Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. 1003 82

Amplification of the MYCN gene is found in a large proportion of neuroblastoma and considered as an adverse prognostic factor. To investigate the effect of ectopic MycN expression on the susceptibility of neuroblastoma cells to cytotoxic drugs we used a human neuroblastoma cell line harboring tetracycline-controlled expression of MycN. Neither conditional expression of MycN alone nor low drug concentrations triggered apoptosis. However, when acting in concert, MycN and cytotoxic drugs efficiently induced cell death. Apoptosis depended on mitochondrial permeability transition and activation of caspases, since the mitochondrion-specific inhibitor bongkrekic acid and the caspase inhibitor zVAD-fmk almost completely abrogated apoptosis. Loss of mitochondrial transmembrane potential and release of cytochrome c from mitochondria preceded activation of caspase-8 and caspase-3 and cleavage of PARP. CD95 expression was upregulated by treatment with cytotoxic drugs, while MycN cooperated with cytotoxic drugs to increase sensitivity to CD95-induced apoptosis and enhancing CD95-L expression. MycN overexpression and cytotoxic drugs also synergized to induce p53 and Bax protein expression, while Bcl-2 and Bcl-X(L) protein levels remained unchanged. Since amplification of MYCN is usually associated with a poor prognosis, these findings suggest that dysfunctions in apoptosis pathways may be a mechanism by which MycN-induced apoptosis of neuroblastoma cells is inhibited.
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PMID:MycN sensitizes neuroblastoma cells for drug-induced apoptosis. 1005 Aug 84


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