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)

Proteasome inhibition leads to accumulation of transcription factors, heat shock proteins, cyclins, and other proteasome substrate proteins by blocking their proteolytic degradation. An increase in gene transcription upon proteasome inhibition was found for a group of proteins, including p21(WAF1/CIP1), ubiquitin, and transcription factors. In this study, we have demonstrated selective up-regulation of extracellular signal-regulated kinase 3 (ERK3) mRNA and protein expression upon treatment with peptide-based proteasome inhibitors or lactacystin. ERK3 is a family member of the mitogen-activated protein kinases (also called ERK) that are key mediators of signal transduction from the cell surface to the nucleus. ERK3 up-regulation is independent of the p53, Bcl2, and caspase 3 status of cells. p38 pathway kinase inhibitors prevent proteasome-dependent ERK3 induction and enhance the antiproliferative effect of proteasome inhibitors. MCF-7 cells expressing ERK3 ectopically show increased resistance toward proteasome inhibition. The results indicate that ERK3 expression is a consequence of p38 pathway activation and most probably represents an intracellular defense or rescue mechanism against cell stress and damage induced by proteasome inhibition.
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PMID:Proteasome- and p38-dependent regulation of ERK3 expression. 1114 4

Cytotoxic drugs commonly used in cancer therapy promote tumor cell death by inducing apoptosis, but the cell death pathway(s) is likely dependent on the mechanism of drug action. In the present study, we investigated the mechanisms of cell death induced by doxorubicin (DXR) and the novel disaccharide anthracycline MEN 10755, in a human ovarian cancer cell line (A2780). Exposure to either anthracycline induced the up-regulation of several genes known to promote cell cycle arrest and DNA repair (WAF1/p21, GADD45) or apoptosis (bax, Fas). Although the expression of Fas was increased, an antagonistic anti-Fas antibody ZB4 did not inhibit anthracycline-induced apoptosis, suggesting that the stimulation of the Fas receptor did not play a critical role in the induction of apoptosis in this cell line. We also observed that neither MEN 10755 nor DXR were able to induce apoptosis in A2780 cells deprived of the nucleus but retaining an intact mitochondrial function (cytoplasts) and that apoptosis induced by either anthracycline was inhibited by cycloheximide, indicating that it is an active process requiring new protein synthesis. Both the caspases inhibitors, ZVAD-fmk and DEVD-cho, inhibited at similar extent apoptosis induced by either DXR or MEN 10755, suggesting an involvement of caspase-3 in this response. We conclude that, in a tumor cell line of epithelial origin, the apoptosis following exposure to anthracyclines is an active process requiring protein synthesis and drug interaction with nuclear structures. The pathway was Fas-independent but likely involved bax and caspase-3 as effectors of the cascade culminating in apoptosis.
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PMID:Apoptotic events in a human ovarian cancer cell line exposed to anthracyclines. 1116 Jun 8

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.
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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

Mouse leukemia L1210 cells selected for resistance to deoxyadenosine contain ribonucleotide reductase that is not feedback inhibited by dATP. These deoxyadenosine-resistant cells (Y8) also do not express p53 protein but do have WAF1 and Gadd45 mRNA and protein. The Y8 cells show increased sensitivity to DNA damaging agents and kinase inhibitors. In these studies we show that in the presence of sodium salicylate (NaSal), the parental wild-type (WT) cells block in G2/M phase of the cell cycle while the Y8 cells show a marked increased in the G0/G1 population of cells. The Y8 cells are more sensitive to apoptosis induced by NaSal than the WT cells. NaSal treatment causes the induction of caspase-3-like activity in Y8 cells but no induction of caspase-3 activity in the WT cells. The caspase inhibitor, Ac-DEVD-CHO, decreased the percentage of Y8 cells in the early apoptotic fraction, but this decrease was reflected by an increase in the percent of cells in the late apoptotic/necrotic fraction. SB20358, a p38-MAP kinase inhibitor did not protect the Y8 cells from NaSal-induced apoptosis indicating that the p38-MAP kinase pathway was not involved in the NaSal-induced apoptotic pathway in the p53-independent Y8 cells.
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PMID:Increased sensitivity to sodium salicylate-induced apoptosis in drug-resistant leukemia L1210 cells. 1129 31

Apoptotic regulation of monocytes/macrophages appears to be closely associated with chronic inflammatory reactions. Since it was demonstrated earlier that certain bacterial cell components are involved in apoptotic regulation of these cells, in the present study, we investigated whether the bacterial fimbria, an important cell structure involved in bacterial adherence to host cells, regulates apoptosis of human monocytic THP-1 cells induced under growth factor deprivation. To investigate this point, we used fimbriae of Porphyromonas gingivalis, a pathogen causing periodontal disease, which is a chronic inflammatory disease. The fimbriae inhibited apoptosis of the cells under growth factor deprivation. This inhibitory action of the fimbriae was completely neutralized by anti-fimbrial antibody. The fimbriae stimulated activation of extracellular signal-regulated kinase (ERK) and expression of cyclin-dependent kinase inhibitor p21 Cip/WAF1 (p21) in the cells. The stimulatory effect of the fimbriae on the expression of the p21 protein was inhibited by treatment with PD98059, a specific inhibitor of ERK. The cell apoptosis was inhibited by treatment with Ac-DEVD-CHO, an inhibitor of caspase-3. The fimbriae inhibited the serum withdrawal-induced cleavage of the caspase-3 proform and poly(ADP-ribose) polymerase, one of the caspase-3 substrates. Furthermore, PD98059 and antisense p21 oligonucleotide blocked the fimbrial inhibition of apoptosis and caspase-3 activation of the cells induced by serum withdrawal. These results show that the bacterial fimbriae inhibited apoptosis of THP-1 cells induced under growth factor deprivation via ERK-dependent expression of p21. The present study suggests that bacterial fimbriae act as potent regulators of chronic inflammatory disease, e.g., periodontal disease, through blocking apoptosis of monocytes/macrophages.
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PMID:Porphyromonas gingivalis fimbriae inhibit caspase-3-mediated apoptosis of monocytic THP-1 cells under growth factor deprivation via extracellular signal-regulated kinase-dependent expression of p21 Cip/WAF1. 1144 72

Oxidative injuries including apoptosis can be induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS) in aerobic metabolism. We determined impacts of a selenium-dependent glutathione peroxidase-1 (GPX1) on apoptosis induced by diquat (DQ), a ROS (superoxide) generator, and peroxynitrite (PN), a potent RNS. Hepatocytes were isolated from GPX1 knockout (GPX1-/-) or wild-type (WT) mice, and treated with 0.5 mm DQ or 0.1-0.8 mm PN for up to 12 h. Loss of cell viability, high levels of apoptotic cells, and severe DNA fragmentation were produced by DQ in only GPX1-/- cells and by PN in only WT cells. These two groups of cells shared similar cytochrome c release, caspase-3 activation, and p21(WAF1/CIP1) cleavage. Higher levels of protein nitration were induced by PN in WT than GPX1-/- cells. Much less and/or slower cellular GSH depletion was caused by DQ or PN in GPX1-/- than in WT cells, and corresponding GSSG accumulation occurred only in the latter. In conclusion, it is most striking that, although GPX1 protects against apoptosis induced by superoxide-generator DQ, the enzyme actually promotes apoptosis induced by PN in murine hepatocytes. Indeed, GSH is a physiological substrate for GPX1 in coping with ROS in these cells.
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PMID:Opposite roles of selenium-dependent glutathione peroxidase-1 in superoxide generator diquat- and peroxynitrite-induced apoptosis and signaling. 1156 67

Cepharanthin is one of the biscoclaurine alkaloids widely used for treatment of many acute and chronic diseases; snakebite, bronchial asthma, alopecia areata, leukopenia during radiation therapy or anticancer treatment. Recently, it has been reported that cepharanthin exerts antitumour effects by increasing immunological competence of the host or apoptosis-inducing activity. In this study, we examined the antitumour effects of cepharanthin against a human adenosquamous cell carcinoma cell line (TYS). Treatment of TYS cells with cepharanthin (10 approximately 20 microg/ml) resulted in a significant suppression of cell growth. Moreover, it was found by the flow cytometry analysis, nick end labelling or agarose gel electrophoresis, that G1 arrest and DNA fragmentation occurred in cepharanthin-treated cells. In addition, it was detected that induction of p21(WAF1) protein and activation of caspase 3 protype, which is one of Interleukin-1beta converting enzyme (ICE) family proteases, were detected by Western blotting. The TYS tumour-bearing nude mice were treated with cepharanthin, which was administered subcutaneously (20 mg/kg/day). The cepharanthin treatment results in a significant suppression of tumour growth and an induction of apoptosis. These findings suggest that cepharanthin induces G1 arrest via expression of p21(WAF1) and apoptosis through caspase 3.
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PMID:Characteristics of antitumour activity of cepharanthin against a human adenosquamous cell carcinoma cell line. 1159 74

Vitamin E-succinate (VES) induced HL-60 human leukemia cells to undergo apoptosis. Treatment with VES induced membrane translocation of Fas; cleavages of caspase-3, PARP, and lamin B; hypophosphorylation of retinoblastoma protein; and increase of p21(WAF1) protein level. During the induction of apoptosis, activity of PKC was gradually increased with downregulation of VES-induced ERK activity and accompanied by activation of caspase-3. Inhibition of PKC by GF109203X blocked VES-mediated membrane translocation of PKC-alpha and cleavage of caspase-3 cascade, resulting in prevention of VES-induced apoptosis. On the contrary, PKC activation by cotreatment with LPC or thapsigargin and VES synergistically increased VES-mediated apoptosis. However, inhibition of ERK activity by PD98059 showed no significant effect on VES-induced PKC activity and apoptosis. Taken together, our data suggest that VES induces activation of PKC and PKC-dependent hypophosphorylation of retinoblastoma protein, which results in induction of apoptosis, and that VES-induced early activation of ERK and ERK-dependent induction of p21(WAF1) are not required for apoptosis.
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PMID:Activation of PKC but not of ERK is required for vitamin E-succinate-induced apoptosis of HL-60 cells. 1168 77

We previously reported that apicidin arrested human cancer cell growth through selective induction of p21(WAF1/Cip1). In this study, the apoptotic potential of apicidin and its mechanism in HL60 cells was investigated. Treatment of HL60 cells with apicidin caused a decrease in viable cell number in a dose-dependent manner and an increase in DNA fragmentation, nuclear morphological change, and apoptotic body formation, concomitant with progressive accumulation of hyperacetylated histone H4. In addition, apicidin converted the procaspase-3 form to catalytically active effector protease, resulting in subsequent cleavages of poly(ADP-ribose) polymerase and p21(WAF1/Cip1). Incubation of HL60 cells with z-DEVD-fmk, a caspase-3 inhibitor, almost completely abrogated apicidin-induced activation of caspase-3, DNA fragmentation, and cleavages of poly(ADP-ribose) polymerase and p21(WAF1/Cip1). Moreover, these effects were preceded by an increase in translocation of Bax into the mitochondria, resulting in the release of cytochrome c and cleavage of procaspase-9. The addition of cycloheximide greatly inhibited activation of caspase-3 by apicidin by interfering with cleavage of procaspase-3 and DNA fragmentation, suggesting that apicidin-induced apoptosis was dependent on de novo protein synthesis. Consistent with these results, apicidin transiently increased the expressions of both Fas and Fas ligand. Preincubation with NOK-1 monoclonal antibody, which prevents the Fas-Fas ligand interaction and is inhibitory to Fas signaling, interfered with apicidin-induced translocation of Bax, cytochrome c release, cleavage of procaspase-3, and DNA fragmentation. Taken together, the results suggest that apicidin might induce apoptosis through selective induction of Fas/Fas ligand, resulting in the release of cytochrome c from the mitochondria to the cytosol and subsequent activation of caspase-9 and caspase-3.
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PMID:Apicidin, a histone deacetylase inhibitor, induces apoptosis and Fas/Fas ligand expression in human acute promyelocytic leukemia cells. 1169 95

AIM:To detect the expression of caspase 3 gene in primary human hepatocellular carcinoma (HCC) and investigate its relationship top21(WAF1) gene expression and HCC apoptosis.METHODS:In situ hybridization was employed to determine caspase 3 and p21(WAF1) expression in HCC.In situ end-labeling was used to detect hepatocytic apoptosis in HCC.RESULTS:Twenty-one of 39 (53.8%) cases of HCC were found to express caspase 3 transcripts, while 46.2% of HCC failed to express caspase 3.Non-cancerous adjacent liver tissues showed more positive caspase 3(87.5%, 7/8) as compared with HCC (p < 0.05). The expression of caspase 3 is correlated with HCC differentiation, 72.2% (13/18) of moderately to highly differentiated HCC showed caspase 3 transcripts positive, while only 38.1% of poorly differentiated HCC harbored caspase 3 transcripts (italic>p < 0.05). No relationship was found between caspase 3 expression and tumor size or grade or metastasis, although 62.5% (5/8) of HCC with metastasis were caspase 3 positive and a little higher than that with no metastasis (51.6%, p> 0.05). Expression of caspase 3 alone did not affect the apoptosis index (AI) of HCC. The AI was 7.12 in caspase 3 positive tumors (n = 21), while in caspase 3-negative cases (n = 18) 6.59 (italic>p > 0.05). Expression of caspase 3 clearly segregated with p21(WAF1) positive tumors as compared with p21(WAF1) negative cases (16 of 23, 69.6% versus 5 of 16, 31.3%) with statistical significance (p = 0.017).In the cases with positive caspase 3 and negative p21(WAF1), the AI was found slightly higher, but with no statistical significance, than that with expres-sion of p21(WAF1) and caspase 3 (7.21 vs 6.98 , p>0.05).CONCLUSION:Loss of caspase 3 expression may contribute to HCC carcinogenesis, although the expression of caspase 3 does not correlate well with cell apoptosis in HCC.p21(WAF1) may be merely one of the inhibitors which can reduce caspase 3 mediated cell apoptosis in HCCs.
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PMID:Analysis of in vivo patterns of caspase 3 gene expression in primary hepatocellular carcinoma and its relationship to p21(WAF1) expression and hepatic apoptosis. 1181 97


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