Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of acacetin-induced apoptosis of human breast cancer MCF-7 cells was investigated. Acacetin caused 50% growth inhibition (IC50) of MCF-7 cells at 26.4% 0.7% M over 24 h in the MTT assay. Apoptosis was characterized by DNA fragmentation and an increase of sub-G1 cells and involved activation of caspase-7 and PARP (poly-ADP-ribose polymerase). Maximum caspase 7 activity was observed with 100 microM acacetin for 24 h. Caspase 8 and 9 activation cascades mediated the activation of caspase 7. Acacetin caused a reduction of Bcl-2 expression leading to an increase of the Bax:Bcl-2 ratio. It also caused a loss of mitochondrial membrane potential that induced release of cytochrome c and apoptosis inducing factor (AIF) into the cytoplasm, enhancing ROS generation and subsequently resulting in apoptosis. Pretreatment of cells with N-acetylcysteine (NAC) reduced ROS generation and cell growth inhibition, and pretreatment with NAC or a caspase 8 inhibitor (Z-IETD-FMK) inhibited the acacetin-induced loss of mitochondrial membrane potential and release of cytochrome c and AIF. Stress-activated protein kinase/c-Jun NH4-terminal kinase 1/2 (SAPK/ JNK1/2) and c-Jun were activated by acacetin but extracellular-regulated kinase 1/2 (Erk1/2) nor p38 mitogen-activated protein kinase (MAPK) were not. Our results show that acacetin-induced apoptosis of MCF-7 cells is mediated by caspase activation cascades, ROS generation, mitochondria-mediated cell death signaling and the SAPK/JNK1/2-c-Jun signaling pathway, activated by acacetin-induced ROS generation.
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PMID:Acacetin-induced apoptosis of human breast cancer MCF-7 cells involves caspase cascade, mitochondria-mediated death signaling and SAPK/JNK1/2-c-Jun activation. 1784 3

Breast cancer is the most common neoplasm in women and is the leading cause of cancer-related death for women. Therefore, new agents targeting prevention and treatment of breast cancer are urgently needed. The present study first investigates that a novel triterpenoid Methyl 25-Hydroxy-3-oxoolean-12-en-28-oate (AMR-Me) derived from 25-Hydroxy-3-oxoolean-12-en-28-oic acid (AMR) is a potent inhibitor of cell growth by inducing human breast cancer MCF-7 cells to undergo apoptosis. AMR-Me induced DNA fragmentation and PARP degradation which were preceded by changing Bax/Bcl-2 ratios, cytochrome c release, and subsequent induction of pro-caspase-9 and -7 processing in breast carcinoma MCF-7 cells, but it did not act on Fas/Fas ligand pathways and the activation of caspase-8, suggesting AMR-Me triggered the mitochondrial apoptotic pathway. The general caspase blocking peptide VAD partially blocked AMR-Me induced apoptosis. AMR-Me stimulated p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase (JNK), but not extracellular signal-regulated kinase activation during apoptosis. SP600125, a specific inhibitor for JNK and SB203580, a p38 MAPK-specific inhibitor suppressed AMR-Me induced apoptosis indicating that activation of JNK and p38 MAPKs involved in the mitochondrial activation-mediated cell death pathway. Our results suggest that AMR-Me can utilize two different MAPK signaling pathways for amplifying the apoptosis cascade, is critical for both our understanding of cell death events and development of cancer preventive/therapeutic agents.
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PMID:Novel synthetic triterpenoid methyl 25-hydroxy-3-oxoolean-12-en-28-oate induces apoptosis through JNK and p38 MAPK pathways in human breast adenocarcinoma MCF-7 cells. 1805 3

Taxol (paclitaxel) is a new antineoplastic drug that has shown promise in the treatment of different tumor types. However, the molecular mechanisms governing taxol-induced apoptosis are poorly understood. Activation of mitogen-activated protein (MAP) kinases is induced by a wide variety of external stress signals and may lead to apoptosis. Therefore, we challenged the human melanoma cell lines A375 and BLM with taxol and characterized the molecular mechanisms regulating taxol-induced apoptosis. Taxol resulted in the activation of apoptosis signal regulated kinase (ASK)1, c-jun NH(2)-terminal kinase (JNK), p38(MAPK) and extracellular-regulated kinase (ERK) together with the downregulation of uncoupling protein 2 (UCP2). In addition, reactive oxygen species (ROS) were induced and DNA-binding activity of the transcription factors AP-1, ATF-2 and ELK-1 was enhanced. Ultimately, cytochrome c was released, and caspases-9 and -3 as well as PARP were cleaved. Pretreatment of melanoma cells with the JNK inhibitor (SP600125) or the p38 inhibitor (SB203580) blocked taxol-induced UCP2 downregulation, ROS generation and apoptosis, whereas the ERK inhibitor (PD98059) had no such effect. Our data provide evidence that taxol-induced mitochondrial stress occurs through the activation of both JNK and p38 pathways, and suggest a novel role for UCP2 in the modulation of taxol-induced apoptosis of melanoma cells.
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PMID:Taxol-induced mitochondrial stress in melanoma cells is mediated by activation of c-Jun N-terminal kinase (JNK) and p38 pathways via uncoupling protein 2. 1806 34

It is reported that diesel exhaust particles contain more 1-nitropyrene (1-NP) than benzo[a]pyrene (B[a]P), both of which are potent carcinogenic compounds. In this study, we show that 1-NP is more potent in reducing cell viability than B[a]P, pyrene, nitrobenzene, and nitromethane. Aldo-keto reductases (AKRs) are enzymes which metabolize polycyclic aromatic hydrocarbons into active metabolites that form PAH-DNA-adducts causing mutagenesis of DNA. We found that the AKR1C2 inhibitor, ursodeoxycholic acid (UA), inhibited 1-NP-induced, but not B[a]P-induced, phosphorylation of p53 and cleavage of poly (ADP-ribose) polymerase (PARP). 1-NP-induced apoptosis was also suppressed by UA, as detected by Hoechst 33342 staining, flow cytometric analysis of subG0/G1 phase and annexin V binding to phosphatidylserine. The AKR1C1 and 1C4 inhibitor, 1,10-phenanthroline (Phen), inhibited the toxic effects of both 1-NP and B[a]P. In contrast, the AKR7A1 and 7A5 inhibitors, succinate and citrate, did not influence the toxic effects of 1-NP or B[a]P. In addition, several metabolic and signaling pathways were analyzed, these were used to compare the results of the toxic effect of AKRs on 1-NP and B[a]P. Through the application of kinase inhibitors, results indicated that p38-MAPK, but not ERK1/2 or JNK, was essential for mediating both 1-NP's and B[a]P's induction of the phosphorylation of p53 and cleavage of PARP. Neither ellipticine, a CYP1A1 inhibitor, nor 2,6-diisopropylphenol, a CYP1A2 and 2B1 inhibitor, blocked the toxic effects of 1-NP and B[a]P, which indicates that neither CYP1A1, 1A2, nor 2B1 is essential for the transformation of 1-NP and B[a], into toxic metabolites. AKR1C2 was constitutively expressed in HepG2 cells and was not regulated by 1-NP or B[a]P. In conclusion, this is the first report on AKRs' actions toward nitro-PAH in cells. The metabolic and signaling pathways for the toxic effects of both 1-NP and B[a]P are similar except that AKR1C2 plays differential role between them. The results provide valuable information for further investigations on AKRs.
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PMID:Aldo-keto reductase 1C2 is essential for 1-nitropyrene's but not for benzo[a]pyrene's induction of p53 phosphorylation and apoptosis. 1820

The primary objective of this study was to determine the possible apoptotic cell death preventive effects of the antioxidant selenium using an experimental rat spinal cord injury (SCI) model and cultured spinal cord-derived neural progenitor cells (NPCs). Sodium selenite treatment exerted a profound preventive effect on apoptotic cell death, including p-P38, p-SAPK/JNK, caspases, and PARP activity, and ameliorated astrogliosis and hypomyelination, which occurs in regions of active cell death in the spinal cords of SCI rats. The foremost protective effect of selenite in SCI would therefore be manifested in the suppression of acute secondary apoptotic cell death. However, selenite does not appear to exert an anti-inflammatory function associated with active microglia and macrophage propagation or infiltration into the lesion site. Selenite-mediated neuroprotection has been linked to selenite's attenuation or inhibition of p38 mitogen-activated protein kinase, pSAPK/JNK, and Bax activation in in vitro and in vivo SCI lesion sites. Selenite also attenuated cell death via the prevention of cytochrome c release, caspase activation, and ROS accumulation in the cytosol. Also, our study showed that selenite administered immediately after SCI significantly diminishes functional deficits. The selenite-treated group recovered hind limb reflexes more rapidly, and a higher percentage of these rats regained responses to a greater degree than was seen in the untreated injured rats. Our data indicate that the therapeutic outcome of selenite is most likely the consequence of its comprehensive apoptotic cell death blocking effects, resulting in the protection of white matter, oligodendrocytes, and neurons, and the inhibition of astrogliosis. The finding that the administration of selenite prevents secondary pathological events in traumatic spinal cord injuries, and promotes the recovery of motor function in an animal model. Its efficacy may facilitate the development of novel drug targets for the treatment of SCI.
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PMID:Selenium attenuates ROS-mediated apoptotic cell death of injured spinal cord through prevention of mitochondria dysfunction; in vitro and in vivo study. 1820 89

Combined treatment with quercetin and TRAIL induced cytotoxicity and enhanced annexin V staining and poly (ADP-ribose) polymerase (PARP) cleavage in human prostate cancer cell lines DU-145 and PC-3. These indicators of apoptosis resulted from the activation of caspase-8, -9, and -3. Although the expression levels of FLIPs, cIAP1, cIAP2, and the Bcl-2 family were not changed in quercetin-treated cells, significant downregulation of survivin occurred. Knockdown survivin by siRNA significantly increased TRAIL-induced apoptosis. We hypothesized that quercetin-induced activation of MAPK (ERK, p38, JNK) is responsible for downregulation of survivin gene expression. To test this hypothesis, we selectively inhibited MAPK during treatment with quercetin. Our data demonstrated that inhibitor of ERK (PD98059), but not p38 MAPK (SB203580) or JNK (SP600125), significantly maintained the intracellular level of survivin during treatment with quercetin. Interestingly, PD98059 also prevented quercetin-induced deacetylation of histone H3. Data from survivin promoter activity assay suggest that the Sp1 transcription factor binds to the survivin promoter region and quercetin inhibits its binding activity through deacetylation of histone H3. Quercetin-induced activation of the ERK-MSK1 signal transduction pathway may be responsible for deacetylation of histone H3. Taken together, our findings suggest that quercetin enhances TRAIL induced apoptosis by inhibition of survivin expression, through ERK-MSK1-mediated deacetylation of H3.
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PMID:Quercetin augments TRAIL-induced apoptotic death: involvement of the ERK signal transduction pathway. 1837 72

Benzo[a]pyrene (BaP) is a potentially genotoxic and cytotoxic environmental pollutant. Previous studies showed that exposure of HepG(2) cells to BaP causes necrotic cell death [Lin, T., Yang, M.S., 2007b. Cell death induced by benzo[a]pyrene in the HepG(2) cells is dependent on PARP-1 activation and NAD depletion. Toxicology 245, 147-153]. In the present study, the signaling pathways associated with this response was studied. BaP induced accumulation and activation of p53 in HepG(2) cells, which occurred as early as 12h after exposure. Activation of p53 was evidenced by its phosphorylation at serine 15 (Ser15) and acetylation at lysine 382 (Lys382). Chemical inhibition and siRNA-mediated knockdown of p53 expression suppressed its phosphorylation as well as cell death. BaP also activated p38 MAPK and ERK, but not JNK, at 6h after exposure. SB203580 and PD98059, specific inhibitors of p38 MAPK and ERK, respectively, suppressed phosphorylation of p53 at Ser15, but the accumulation of p53 was only moderately reduced. Acetylation of p53 at Lys 382 was not affected by these inhibitors, suggesting that acetylation stabilizes p53 in response to DNA damage. SB203580 and PD98059 prevented downstream energy failure and BaP-induced cell death. Similar results were obtained with siRNA against two isoforms of p38 MAPK, p38alpha and p38beta. Wortmannin, selective inhibitor of DNA-PK and ATM/ATR, abolished p53 phosphorylation, indicating an involvement of multiple pathways of p53 phosphorylation upon exposure to BaP. In summary, the current study demonstrated that both MAPK and p53 activation are required for BaP-induced necrotic cell death. The results also provide a novel model for studying the regulation between p53 and p38 MAPK in the progression of cellular necrosis.
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PMID:MAPK regulate p53-dependent cell death induced by benzo[a]pyrene: involvement of p53 phosphorylation and acetylation. 1840 7

We investigated the response of alphaB-crystallin to oxidative stress and calpain inhibition in an attempt to elucidate the signalling pathways mediating its phosphorylation. Given the high expression levels of alphaB-crystallin in cardiac muscle one can evaluate the significance of its participation in preservation of homeostasis under adverse conditions. H9c2 cardiac myoblasts were used as our experimental model since their response reflects the signal transduction pathways activated by stress conditions in the myocardium. Thus, in H9c2 cells treated with H2O2 the mechanism regulating alphaB-crystallin phosphorylation was found to involve p38-MAPK/MSK1 as well as intracellular free calcium levels. Our immunocytochemical experiments demonstrated phosphorylated alphaB-crystallin to be co-localized with tubulin, potentially preserving cytoskeletal architecture under these interventions. In H9c2 cells treated with calpain inhibitors (ALLN, ALLM) alphaB-crystallin exhibited a p38-MAPK- and [Ca 2+](i)-dependent phosphorylation pattern since the latter was ablated in the presence of the selective p38-MAPK inhibitor SB203580 and calcium chelator BAPTA-AM. Calpain activity repression ultimately led to apoptosis confirmed by PARP fragmentation and chromatin condensation. However, the apoptotic pathway activated by ALLM and ALLN differed, underlying the diverse transduction mechanisms stimulated. In addition to this, an anti-apoptotic role for phospho-alphaB-crystallin was verified by confirmation of its interaction with pro-caspase 3, hindering its cleavage and subsequent activation. Collectively, our findings underline alphaB-crystallin crucial role as a participant of cardiac cells early response to stressful stimuli compromising their survival.
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PMID:Oxidative stress and calpain inhibition induce alpha B-crystallin phosphorylation via p38-MAPK and calcium signalling pathways in H9c2 cells. 1842 Mar 82

The cell proliferation of p53-deficient Jurkat T cells is controlled after prolonged exposure to human lactoferrin (Lf). However, the molecular mechanism by which Lf influences these cellular responses remains unclear. In this study, we demonstrate that Lf-induced apoptosis in Jurkat T cells occurs in a dose- and time-dependent manner via the regulation of c-Jun N-terminal kinase (JNK) activity. Jurkat cells exposed to Lf for 1 day, especially at concentrations in excess of 500 microg/ml, showed typical apoptosis, as indicated by decreased cell viability and increased Annexin V binding. Our results also showed that Lf induced the activation of caspase 9 and caspase 3 activation, as demonstrated by our detection of cleaved caspases and PARP. Lf-induced apoptosis did not influence Bcl-2 expression via an ERK1/2 phosphorylation pathway, but was rather associated with the level of Bcl-2 phosphorylation. The treatment of cells with the specific JNK inhibitor SP600125, but not the p38 MAPK inhibitor SB203580, revealed that the JNK-Bcl-2 signaling cascade is required for Lf-induced apoptosis. When JNK activation was abolished by SP600125, no Bcl-2 phosphorylation was detected, and the Lf-treated Jurkat cells did not undergo cell death. These findings indicate that Lf functions as a biological mediator of apoptosis in the human leukemia Jurkat T-cell line, via the JNK-associated Bcl-2 signaling pathway.
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PMID:Requirement of the JNK-associated Bcl-2 pathway for human lactoferrin-induced apoptosis in the Jurkat leukemia T cell line. 1853 98

Waldenstrom macroglobulinaemia (WM) is an incurable lymphoplasmacytic lymphoma with secretion of serum monoclonal immunoglobulin M (IgM). We previously showed that patients receiving cholesterol-lowering statins, had the lowest IgM value in a large cohort of patients with WM. Simvastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor, induced inhibition of proliferation, cytotoxic effect and apoptosis in IgM secreting cell lines as well as in primary CD19(+) WM cells. Interestingly, those effects were reversed by addition of mevalonate and geranylgeranylpyrophosphate, demonstrating that simvastatin inhibited cell growth, survival and IgM secretion on BCWM.1 WM cells by inhibition of geranylgeranylated proteins. Furthermore, simvastatin overcame tumour cell growth induced by co-culture of WM cells with bone-marrow stromal cells. Simvastatin also decreased IgM secretion by BCWM.1 cells at an early time-point that had not affected cell survival. Simvastatin-induced cytotoxicity was preceded by a decrease in Akt (protein kinase B, PKB) and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathways at 18 h. In addition, simvastatin induced an increase in stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) MAPK followed by caspase-8, -9, -3 and poly(ADP-ribose) polymerase (PARP) cleavages at 18 h, leading to apoptosis. Furthermore, simvastatin enhanced the cytotoxicity induced by bortezomib, fludarabine and dexamethasone. Our studies therefore support our earlier observation of statin-mediated anti-WM activity and provide the framework for future clinical trials testing simvastatin in WM.
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PMID:The HMG-CoA inhibitor, simvastatin, triggers in vitro anti-tumour effect and decreases IgM secretion in Waldenstrom macroglobulinaemia. 1853 66


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