Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.62 (caspase-9)
7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic trioxide (As2O3) has been shown to inhibit the proliferation of hematologic malignant cells. Previously, we reported that As2O3 had an antitumoral effect in head and neck cancer. Here, we investigated the induction of apoptosis and its mechanism in PCI-1 head and neck squamous carcinoma cells, after treatment with As2O3. Treatment with 2 microM of As2O3 caused apoptosis in PCI-1 cells following 3 days of exposure, which was detected by the annexin V-PI and DAPI staining methods. The cell death population was markedly increased, being 88% larger than the As2O3-untreated control cells. To address the mechanism of apoptosis, a Western blot assay was performed, showing that Bax was up-regulated without a change in Bcl-2. Activation of caspase-9 during As2O3-induced apoptosis was substantiated by monitoring the proteolysis of the caspase-9, which was associated with an increase of Apaf-1 and cytochrome c protein. PCI-1 cells rapidly changed the mitochondria membrane potential (DeltaPsim) after addition of As2O3. Furthermore, activation of caspase-3 was demonstrated by monitoring the proteolysis of the caspase-3 and by measuring caspase-3 activity with a fluorogenic substrate, which was associated with the cleavage of poly(ADP-ribose) polymerase. To examine the in vivo effect of As2O3, C3H mouse inoculated with syngenic SCC7 cells was treated by intratumoral injection of As2O3 (300 microg) every day, demonstrating that tumor mass was dramatically reduced on day 4, and revealed induction of apoptosis by TUNEL assay. These results suggest that apoptosis of PCI-1 cells by As2O3 is induced by activation of caspase-3 via cytochrome c, caspase-9 and Apaf-1 complex.
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PMID:Potential role of caspase-3 and -9 in arsenic trioxide-mediated apoptosis in PCI-1 head and neck cancer cells. 1117 89

This study examined the growth inhibitory effects of theasinensin A (from oolong tea) and black tea polyphenols, including theaflavin (TF-1), a mixture (TF-2) of theaflavin-3-gallate (TF-2a) and theaflavin-3'-gallate (TF-2b), and theaflavin-3,3'-digallate (TF-3) in human cancer cells. Theasinensin A, TF-1, and TF-2 displayed strong growth inhibitory effects against human histolytic lymphoma U937, with estimated IC50 values of 12 microM, but were less effective against human acute T cell leukemia Jurkat, whereas TF-3 and (-)-epigallocatechin-3-gallate (EGCG) had lower activities. The molecular mechanisms of tea polyphenol-induced apoptosis as determined by annexin V apoptosis assay, DNA fragmentation, and caspase activation were further investigated. Loss of membrane potential and reactive oxygen species (ROS) generation were also detected by flow cytometry. Treatment with tea polyphenols caused rapid induction of caspase-3, but not caspase-1, activity and stimulated proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). Pretreatment with a potent caspase-3 inhibitor, Z-Asp-Glu-Val-Asp-fluoromethyl ketone, inhibited theasinensin A induced DNA fragmentation. Furthermore, it was found that theasinensin A induced loss of mitochondrial transmembrane potential, elevation of ROS production, release of mitochondrial cytochrome c into the cytosol, and subsequent induction of caspase-9 activity. These results indicate that theasinensin A allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA and induces DFF-45 (DNA fragmentation factor) degradation. The results suggest that induction of apoptosis by theasinensin A may provide a pivotal mechanism for their cancer chemopreventive function.
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PMID:Induction of apoptosis by the oolong tea polyphenol theasinensin A through cytochrome c release and activation of caspase-9 and caspase-3 in human U937 cells. 1131 5

To identify the genes involved in cervical carcinogenesis, we applied the mRNA differential display method and identified a candidate tumor suppressor gene, HCCS-1, which was present in normal cervical tissue but absent in cervical cancer, metastatic lymph node and CUMC-6 cervical cancer cell line. HCCS-1 transcripts were expressed in many normal tissues including leukocyte, lung, spleen, liver, heart and uterine cervix. Its expression was absent in 8 human cancer cell lines. HCCS-1-transfected HeLa cells exhibited growth inhibition by about 50%. This inhibitory effect of HCCS-1 on cervical cancer cells was associated with apoptotic process including DNA fragmentation. HCCS-1-transfected HeLa cells were shown to release cytochrome c from mitochondria, which activates caspase-9 and -3 and finally results in cleavage of poly(ADP-ribose) polymerase. Apoptosis formation was detected by propidium-iodide/annexin V. HCCS-1-transfected HeLa cells were more sensitive to adriamycin or UVC ray triggered apoptosis. These results suggest that HCCS-1 is downregulated in multiple human tumor types and may serve as a candidate tumor suppressor gene through apoptotic pathway against human cervical cancer.
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PMID:Candidate tumor suppressor, HCCS-1, is downregulated in human cancers and induces apoptosis in cervical cancer. 1185 54

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.
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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

Methamphetamine is a neurotoxic drug of abuse known to cause cell death both in vitro and in vivo. Nevertheless, the molecular and cellular mechanisms involved in this process remain to be clarified. Herein, we show that methamphetamine-induced apoptosis is associated with early (2 h) overexpression of bax, decreases of mitochondrial membrane potential and oxygen consumption as well as release of cytochrome c from mitochondria. In addition, activated caspase-9 was detected at 4 h post-METH exposure. Cell death was detectable by annexin V and propidium iodide staining after 8 h of methamphetamine exposure. At that time, the majority of the cells were stained by annexin V alone, with some cells being stained for both annexin V and propidium iodide. Moreover, cleavage of caspase-3, poly (ADP-ribose) polymerase and DNA fragmentation-related factor 45 was detected at 8 h post drug treatment. These results indicate that methamphetamine-induced apoptotic cell death results from early overexpression of bax, reduction of mitochondrial respiration and membrane potential and release of mitochondrial cytochrome c with subsequent activation of the caspase cascade.
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PMID:Methamphetamine induces apoptosis in an immortalized rat striatal cell line by activating the mitochondrial cell death pathway. 1201 10

All human melanoma cell lines (assessed by annexin V and TUNEL assays) were resistant to apoptosis induction by TRAIL/Apo2L protein. TRAIL/Apo2L activated caspase-8 and caspase-3, but subsequent apoptotic events such as poly(ADP-ribose) polymerase cleavage and DNA fragmentation were not observed. To probe the molecular mechanisms of cellular resistance to apoptosis, melanoma cell lines were analyzed for expression of apoptosis regulators (apoptotic protease-associated factor-1, FLIP, caspase-8, caspase-9, caspase-3, cellular inhibitor of apoptosis, Bcl-2, or Bax); no correlation was observed. TRAIL/Apo2L was induced in melanoma cell lines by IFN-beta and had been correlated with apoptosis induction. Because IFN-beta induced other gene products that have been associated with apoptosis, it was postulated that one or more IFN-stimulated genes might sensitize cells to TRAIL/Apo2L. Melanoma cell lines were treated with IFN-beta for 16-24 h before treatment with TRAIL/Apo2L. Regardless of their sensitivity to either cytokine alone, >30% of cells underwent apoptosis in response to the combined treatment. Induction of apoptosis by IFN-beta and TRAIL/Apo2L in combination correlated with synergistic activation of caspase-9, a decrease in mitochondrial potential, and cleavage of poly(ADP-ribose) polymerase. Cleavage of X-linked inhibitor of apoptosis following IFN-beta and TRAIL/Apo2L treatment was observed in sensitive WM9, A375, or WM3211 cells but not in resistant WM35 or WM164 cells. Thus, in vitro IFN-beta and TRAIL/Apo2L combination treatment had more potent apoptotic and anti-growth effects when compared with either cytokine alone in melanoma cells lines.
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PMID:IFN-beta pretreatment sensitizes human melanoma cells to TRAIL/Apo2 ligand-induced apoptosis. 1209 88

The apoptotic pathway activated by chimeric anti-CD20 monoclonal antibodies (rituximab, IDEC.C2B8) was analyzed using the Burkitt lymphoma cell line Ramos. Crosslinking of CD20 (CD20XL) induced apoptosis in Ramos cells, which involved loss of mitochondrial membrane potential (Deltapsi(m)), the release of cytochrome-c (cyt-c), and activation of caspases-9 and -3. Nevertheless, several lines of evidence showed that the apoptotic outcome did not depend on these events. First, under circumstances where Ramos cells display resistance to either CD95- or B cell receptor (BCR)-induced apoptosis, CD20XL-induced apoptosis was not affected, pointing to a distinct pathway. Second, the broad-spectrum caspase inhibitor zVAD-fmk prevented processing of caspase-9, -3 and PARP as well as DNA fragmentation, but did not block apoptosis as measured by annexin V staining, cell size and membrane integrity. Lastly, Bcl-2 overexpression blocked cyt-c release and the decrease in Deltapsi(m), and completely prevented CD95- or BCR-mediated apoptosis; however, it did not affect CD20XL-induced cell death. We conclude that although CD20XL can initiate the mitochondrial apoptosis pathway, CD20-induced apoptosis does not necessarily require active caspases and cannot be blocked by Bcl-2. Since most chemotherapeutic drugs require the activation of caspases to exert their cytotoxicity, these findings provide an important rationale for the use of CD20 mAbs in chemoresistant malignancies.
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PMID:CD20-induced B cell death can bypass mitochondria and caspase activation. 1220 Jun 88

To identify molecules involved in the progression of human melanoma to metastatic disease, autologous primary and metastatic melanoma cells were compared by differential mRNA display. One cDNA, expressed in primary but not in autologous metastatic cells in three different patients, was cloned and characterized, and shown to be the human homologue of the inducible, immediate early TDAG51/PHLDA1 (pleckstrin-homology-like domain family A, member1) gene. Monoclonal antibodies produced against the PHLDA1 protein revealed homogeneous strong expression by benign melanocytic nevi, and progressively reduced expression in primary and metastatic melanomas in vivo. Analysis of stable cDNA transfectants in two different cell lines revealed that constitutive PHLDA1 expression is associated with reduced cell growth, cloning efficiency, and colony formation but not with alterations in cell cycle parameters. However, PHLDA1 expression was associated with increased basal apoptosis as assessed by live cell annexin V binding, terminal deoxynucleotidyltransferase-dependent nucleotide incorporation, and with increased cleavage of poly(ADP-ribose) polymerase and caspase-9. Constitutive PHLDA1 expression greatly enhances the sensitivity of human melanoma cells to the chemotherapeutic agents doxorubicin and camptothecin. These results suggest that PHLDA1 is constitutively expressed by melanocytic nevi where it may contribute to their benign phenotype. The progressive loss of PHLDA1 expression in melanomas may play a role in deregulated cell growth and apoptosis resistance in these tumors.
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PMID:Identification of the human PHLDA1/TDAG51 gene: down-regulation in metastatic melanoma contributes to apoptosis resistance and growth deregulation. 1238 58

Macrophages infected with Mycobacterium tuberculosis undergo increased rates of apoptosis. Important objectives are to define the microbial factors that cause apoptosis, the mechanisms involved and the impact on infection. The 19-kDa M. tuberculosis glycolipoprotein (p19) is both cell wall-associated and secreted and is a candidate virulence factor. We investigated the potential of recombinant, His-tagged p19 lacking the secretion/acylation signal to induce macrophage apoptosis. The TUNEL assay and annexin V binding to membrane phosphatidylserine were used to measure apoptosis. The results show that p19 does act to induce apoptosis in differentiated THP-1 cells and monocyte-derived macrophages and that this effect is both dose- and time-dependent. Furthermore, this effect of p19 is Toll-like receptor (TLR)-2-mediated because preincubation of either THP-1 cells or TLR-2-expressing CHO cells with anti-TLR-2 mAb inhibited apoptosis induced by p19. Apoptosis of macrophages in response to p19 was found to be caspase-8 dependent and caspase-9 independent consistent with a transmembrane pathway signaling cell death through TLR-2. The viability of M. tuberculosis in cells undergoing apoptosis induced by p19 was significantly reduced suggesting the possibility that this may favor containment of infection. Although native p19 is a mycobacterial glycolipoprotein, based upon the use of recombinant p19 where the acylation signal had been removed, we conclude that it is the polypeptide component of p19 that is responsible for signaling through TLR-2 and that the lipid moiety is not required.
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PMID:The 19-kDa Mycobacterium tuberculosis protein induces macrophage apoptosis through Toll-like receptor-2. 1259 64

Magnolol, isolated from the stem bark of Magnolia officnalis, was found to inhibit proliferation of human HL-60 cells and Jurkat T leukemia cells via inducing apoptosis in a dose- and time-dependent manner. By contrast, magnolol did not cause apoptosis in neutrophils and peripheral blood mononuclear cells of healthy donors. Apoptosis was determined by detection of DNA fragmentation in gel electrophoresis, morphological alternations by flow cytometry, quantification of phosphatidylserine externalization by Annexin V labeling and oligonucleosomal DNA content by TUNEL labeling. Activation of caspase-9, -3 and -2, and the proteolytic cleavage of poly(ADP-ribose) polymerase were found during apoptosis induced by magnolol. In addition, both pan-caspase and selective caspase-9 inhibitor blocked magnolol-induced apoptosis. The apoptosis could also be partially attenuated by caspase-3 and -2 inhibitors. Magnolol induced the reduction of mitochondrial transmembrane potential and the release of cytochrome c into cytoplasm. In conclusion, our findings indicate that magnolol-induced apoptotic signaling is carried out through mitochondria alternations to caspase-9 and that then the downstream effector caspases are activated sequentially. Magnolol could be a potentially effective drug for leukemia with low toxicity to normal blood cells and it merits further investigation.
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PMID:Magnolol induces apoptosis in human leukemia cells via cytochrome c release and caspase activation. 1263 15


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