UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
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Cardiotonic steroids (CTS) like ouabain are not only specific inhibitors of the sodium pump (Na(+),K(+)-ATPase), they also can influence various cytosolic signaling events in a hormone-like manner. In the neuroblastoma cell line SH-SY5Y ouabain triggers multiple signaling pathways. Within 30 min of incubation with 1 or 10 microM ouabain, SH-SY5Y cells generate reactive oxygen species to a level approximately 50% above control and show a modest but significant elevation in cytosolic [Ca(2+)] of about 25%. After 6 h of exposure, ouabain stimulates a series of anti-apoptotic actions in SH-SY5Y cells, including concentration-dependent phosphorylation of Erk1/2, Akt, and Bad. Nevertheless, at the same time this CTS also induces a series of events that inhibit retinoic acid-induced neuritogenesis and promote cell death. Both of these latter phenomena are possibly associated with the observed ouabain-induced reduction in the abundance of the anti-apoptotic proteins Bcl-XL and Bcl-2. In addition, ouabain treatment results in cytochrome c release into the cytosol and induces activation of caspase 3, events that point towards the stimulation of apoptotic pathways that are probably enhanced by the stimulation of p53 phosphorylation at Ser15 also observed in this study. These pathways may eventually lead to cell death: treatment with 10 nM ouabain results in a 20% decrease in cell number after 4 days of incubation and treatment with 1 microM ouabain decreases cells number by about 75%. The results obtained here emphasize the importance of further research in order to elucidate the various signalling cascades triggered by ouabain and possibly other CTS that are used in the treatment of heart failure and to identify their primary receptor(s).
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PMID:Ouabain activates signaling pathways associated with cell death in human neuroblastoma. 1752 49

Phosphatase and tension homolog located on chromosome ten (PTEN) is a tumor suppressor as it negatively regulates activation of Akt. Mutation or deletion of PTEN has been found in as high as 80% of glioblastomas, which harbor aberrant cell signaling passing through the phosphatidylinositol-3-kinase (PI3K) and Akt (PI3K/Akt) survival pathway. Glioblastoma cells without functional PTEN are not easily amenable to apoptosis. We investigated the possibility of modulation of signal transduction pathways for induction of apoptosis in human glioblastoma T98G (PTEN-harboring) and U87MG (PTEN-deficient) cell lines after treatment with the combination of all-trans retinoic acid (ATRA) and interferon-gamma (IFN-gamma). Treatment with ATRA plus IFN-gamma stimulated PTEN expression and suppressed Akt activation in T98G cells, whereas no PTEN expression but Akt activation in U87MG cells under the same conditions. Pretreatment of U87MG cells with the PI3K inhibitor LY294002 could prevent Akt activation. Interestingly, ATRA plus IFN-gamma could significantly decrease cell viability and increase morphological features of apoptosis in both cell lines. Combination of ATRA and IFN-gamma showed more efficacy than IFN-gamma alone in causing apoptosis that occurred due to increases in Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, and caspase-3 activity. Luciferase reporter gene assay showed that combination of ATRA and IFN-gamma significantly down regulated transcriptional activity of the nuclear factor kappa B (NF-kappaB), a survival signaling factor, in U87MG cells. Thus, combination of ATRA and IFN-gamma caused significant amounts of apoptosis in T98G cells due to suppression of the PI3K/Akt survival pathway while the same treatment caused apoptosis in U87MG cells due to down regulation of the NF-kappaB activity. Therefore, the combination of ATRA and IFN-gamma could modulate different survival signal transduction pathways for induction of apoptosis and should be considered as an effective therapeutic strategy for controlling the growth of both PTEN-harboring and PTEN-deficient glioblastomas.
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PMID:Combination of all-trans retinoic acid and interferon-gamma suppressed PI3K/Akt survival pathway in glioblastoma T98G cells whereas NF-kappaB survival signaling in glioblastoma U87MG cells for induction of apoptosis. 1761 12

Glioblastoma is the deadliest and most prevalent brain tumor, which is not yet amenable to any treatments. Therefore, new and innovative therapeutic strategies need to be developed for treating this deadly disease. We found that all-trans retinoic acid (ATRA) or 13-cis retinoic acid (13-CRA) induced astrocytic differentiation with down regulation of telomerase activity in rat glioblastoma C6 cells and enhanced sensitivity of the cells to interferon-gamma (IFN-gamma) or taxol (TXL) for apoptosis. Sensitivity of differentiated cells to IFN-gamma or TXL was greatly increased for apoptosis with increases in calcineurin expression, Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, and expression and activity of calpain and caspases. Treatment with IFN-gamma activated caspase-8 indicating induction of apoptosis via the receptor-mediated pathway. Notably, IFN-gamma activated the signal transducer and activator of transcription-1 (STAT-1) for signaling via binding to gamma activator sequence (GAS), whereas TXL activated Raf-1 kinase for inactivation of Bcl-2 by its phosphorylation. We confirmed involvement of different proteolytic mechanisms in cell death by pretreating the cells with caspase-8 inhibitor II, calpeptin (calpain inhibitor), and caspase-9 inhibitor I, and caspase-3 inhibitor IV. Results demonstrated that retinoids induced astrocytic differentiation with down regulation of telomerase activity and worked synergistically to enhance sensitivity of cells to the cytotoxic agent IFN-gamma and the cytostatic agent TXL for apoptosis. This combination therapy for differentiation and apoptosis could be highly effective for controlling the malignant growth of glioblastoma.
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PMID:Differentiation decreased telomerase activity in rat glioblastoma C6 cells and increased sensitivity to IFN-gamma and taxol for apoptosis. 1769 33

We have recently reported that PML-RAR-induced misfolding of the N-CoR protein could be reversed by retinoic acid (RA), a therapeutic agent that promotes differentiation of acute promyelocytic leukemia (APL) cells. This finding suggests a role of misfolded N-CoR in the differentiation arrest of APL cells and highlights its significance as a potential molecular target in protein conformation-based therapy for APL. Based on this hypothesis, we investigated the therapeutic potential of several protein conformation modifiers on APL-derived cell lines NB4 and NB4-R1. Through a small-scale screening of these selected compounds, we identified genistein as a potent inhibitor of growth of both RA-sensitive and RA-resistant APL cells. Genistein inhibited the growth of NB4 cells through its collective regulatory effects on cell cycle progression, differentiation, and apoptosis. Genistein-induced apoptosis of NB4 cells was mediated by activation of caspase-9 and caspase-3 and was associated with a decrease in mitochondrial transmembrane potential and cytosolic release of cytochrome c. Genistein promoted differentiation of both RA-sensitive and RA-resistant NB4 cells and induced cell cycle arrest by blocking the G(2)-M transition. Genistein up-regulated the expression of PML and N-CoR proteins, promoted degradation of PML-RAR, and reorganized the microspeckled distribution of PML oncogenic domains to a normal dot-like pattern in NB4 cells. Moreover, genistein significantly reversed the PML-RAR-induced misfolding of N-CoR protein by possibly inhibiting the selective phosphorylation-dependent binding of N-CoR to PML-RAR. These findings identify genistein as a potent modifier of N-CoR protein conformation and highlights its therapeutic potential in both RA-sensitive and RA-resistant APL cells.
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PMID:Therapeutic targeting of nuclear receptor corepressor misfolding in acute promyelocytic leukemia cells with genistein. 1769 21

Glioblastoma is the most prevalent and highly malignant brain tumor that continues to defy current treatment strategies. This investigation used all-trans retinoic acid (ATRA) and taxol (TXL) as a combination therapy for controlling the growth of human glioblastoma T98G xenografted in athymic nude mice. Histopathological examination revealed that ATRA induced differentiation and combination of ATRA and TXL caused more apoptosis than either treatment alone. Combination therapy decreased expression of telomerase, nuclear factor kappa B (NFkappacapital VE, Cyrillic), and inhibitor-of-apoptosis proteins (IAPs) indicating suppression of survival factors while upregulated Smac/Diablo. Combination therapy also changed expression of Bax and Bcl-2 proteins leading to increased Bax:Bcl-2 ratio, mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF), and activation of caspase-9. Increased activities of calpain and caspase-3 degraded 270 kD alpha-spectrin at the specific sites to generate 145 kD spectrin breakdown product (SBDP) and 120 kD SBDP, respectively. Further, increased activity of caspase-3 cleaved inhibitor-of-caspase-activated DNase (ICAD). In situ double immunofluorescent labelings showed overexpression of calpain, caspase-12, caspase-3, and AIF during apoptosis, suggesting involvement of both caspase-dependent and caspase-independent pathways for apoptosis. Our investigation revealed that treatment of glioblastoma T98G xenografts with the combination of ATRA and TXL induced differentiation and multiple molecular mechanisms for apoptosis.
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PMID:Combination of all-trans retinoic acid and taxol regressed glioblastoma T98G xenografts in nude mice. 1770 58

We investigated the in vitro efficacy of all-trans retinoic acid (ATRA) and alpha-tocopherol succinate (alpha-TS) alone and in combination on the induction of cell death in freshly isolated leukemic cells obtained from chronic myeloid leukemia (CML) patients. In vitro cytotoxicity and induction of lipid peroxidation by ATRA (10 microM) and alpha-TS (25 or 50 microM) were evaluated in primary leukemic cells by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and malondialdehyde formation respectively. Treatment of leukemic cells with alpha-TS alone or in combination with ATRA significantly (P < 0.05) decreased the cell viability in a concentration and time dependent manner as compared to peripheral blood mononuclear cells obtained from normal healthy controls. Lipid peroxidation was enhanced by 98% (P < 0.05) on combined treatment of cells with ATRA (10 microM) and alpha-TS (50 microM). ATRA alone did not enhance the externalization of phosphatidyl serine as studied by annexin-V binding using fluorescence activated cell sorter analysis, whereas in combination with alpha-TS it increased to 400% at 12 h. The treatment of leukemic cells to combination of ATRA with alpha-TS significantly decreased (P < 0.05) mitochondrial membrane potential and enhanced lysosomal destabilization. The combination of these drugs also increased mitochondrial and cytosolic reactive oxygen species (ROS) production, nitric oxide levels, and caspase-3 activity significantly and caused DNA fragmentation at 24 h in a concentration dependent manner in the leukemic cells. Our data suggest that ATRA in combination with alpha-TS efficiently induces apoptosis in leukemic cells, which may be a useful therapeutic modality in CML patients.
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PMID:ATRA promotes alpha tocopherol succinate-induced apoptosis in freshly isolated leukemic cells from chronic myeloid leukemic patients. 1787 76

Aberrant cytoplasmic sequestration has been reported as an alternative mechanism of p53 inactivation to mutation in neuroblastoma. We hypothesized that p53 localization and function in neuroblastoma is related to differentiation status. Eighty-two untreated and 24 paired pre and post-chemotherapy neuroblastomas were studied by immunocytochemistry for p53, p21(WAF1), BAX, Bcl2 and Ki67. Predominantly nuclear p53 was detected in undifferentiated neuroblastoma, and both nuclear and cytoplasmic p53 in differentiating neuroblastoma. The nuclear p53 labeling index (LI) correlated with the Ki67 LI (r = 0.51, p <0.001), and weakly with p21(WAF1) (r = 0.37), but not with BAX or Bcl2. There was a significant reduction in p53, p21(WAF1) and Ki67 LI after chemotherapy (p < 0.01), an increase in BAX (p <0.05), but no change in Bcl2. p53 localization and function were examined in two p53 wild-type undifferentiated and 9-cis retinoic acid differentiated neuroblastoma cell lines. Using immunocytochemistry, immunofluorescence and cell fractionation, p53 was found to be predominantly nuclear in both undifferentiated and differentiated cells. Following irradiation, there was upregulation of p53, p21(WAF1) and MDM2, but less induced PARP and caspase 3 cleavage in differentiated cells, suggesting intact p53 transcriptional function, but resistance to apoptosis. p53 function in undifferentiated and differentiated cells was confirmed by upregulation of p21(WAF1) and MDM2 following Nutlin-3 treatment. In conclusion, p53 is predominantly nuclear and functional in neuroblastoma regardless of differentiation status.
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PMID:p53 is nuclear and functional in both undifferentiated and differentiated neuroblastoma. 1791 39

Fenretinide, N-(4-hydroxyphenyl)retinamide (4-HPR) is an aminophenol-containing synthetic retinoid derivative of all-trans-retinoic acid, which is a potent chemopreventive and antiproliferative agent against various cancers. Clinical studies of 4-HPR have shown side effects consisting of night blindness and ocular toxicity. To maintain potent anticancer activity without side effects, p-dodecylaminophenol (p-DDAP) was designed based on structure-activity relationships of 4-HPR. In our study, we investigate whether p-DDAP shows anticancer activity against human prostate cancer cell line PC-3 when compared with 4-HPR. p-DDAP inhibited PC-3 cell growth progressively from low to high concentration in a dose-dependent manner. p-DDAP was the most potent antiproliferative agent in vitro among 6 p-alkylaminophenols and 3 4-hydroxyphenyl analogs examined including 4-HPR. Cells treated with p-DDAP were shown to undergo apoptosis, based on condensation nuclei, cytofluorimetric analysis, propidium iodide staining and the expression of bcl-2 and caspase 3. p-DDAP arrested the S phase of the cell cycle, while 4-HPR arrested the G(0)/G(1) phase. In addition, both the i.v. and i.p. administration of p-DDAP suppressed tumor growth in PC-3-implanted mice in vivo. p-DDAP showed no effects on blood retinol concentrations, in contrast to reductions after 4-HPR administration. These results indicate that p-DDAP exhibits excellent anticancer efficacy against hormonal independent prostate cancer in vitro and in vivo, and it may have great potential for clinical use in the treatment of prostate cancer with reduced side effects.
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PMID:p-Dodecylaminophenol derived from the synthetic retinoid, fenretinide: antitumor efficacy in vitro and in vivo against human prostate cancer and mechanism of action. 1795 89

We hypothesized that induction of differentiation with retinoid could increase sensitivity to microtubule-binding drug taxol (TXL) for apoptosis in human glioblastoma T98G and U87MG cells. Treatment of cells with 1 microM all-trans retinoic acid (ATRA) or 1 microM 13-cis retinoic acid (13-CRA) for 7 days induced astrocytic differentiation, overexpression of glial fibrillary acidic protein (GFAP), and also down regulated telomerase expression and activity, thereby increased sensitivity to TXL for apoptosis. Treatment of glioblastoma cells with TXL triggered production of reactive oxygen species (ROS), induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), and activated the redox-sensitive c-Jun NH(2)-terminal kinase 1 (JNK1) pathway. Moreover, TXL activated Raf-1 kinase for phosphorylation and inactivation of anti-apoptotic Bcl-2 protein. The events of apoptosis included increase in expression of Bax, down regulation of Bcl-2 and baculoviral inhibitor-of-apoptosis protein (IAP) repeat containing (BIRC) proteins, mitochondrial release of cytochrome c and Smac into the cytosol, increase in intracellular free [Ca(2+)], and activation of calpain, caspase-9, and caspase-3. Increased activity of caspase-3 cleaved inhibitor of caspase-activated DNase (ICAD) to release and translocate CAD to the nucleus for DNA fragmentation. Involvement of stress signaling kinases and proteolytic activities of calpain and caspase-3 in apoptosis was confirmed by pretreating cells with specific inhibitors. Taken together, our results suggested that retinoid (ATRA or 13-CRA) induced astrocytic differentiation with down regulation of telomerase activity to increase sensitivity to TXL to enhance apoptosis in glioblastoma cells. Thus, combination of retinoid and TXL could be an effective therapeutic strategy for controlling the growth of glioblastoma.
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PMID:Retinoids induced astrocytic differentiation with down regulation of telomerase activity and enhanced sensitivity to taxol for apoptosis in human glioblastoma T98G and U87MG cells. 1798 64

Geranylgeranoic acid (GGA) and 2,3-dihydrogeranylgeranoic acid (2,3-diGGA) are geranylgeraniol-derived metabolites (Kodaira et al. (2002) J Biochem 132: 327-334). In the present study, we examined the effects of these acids on HL-60 cells. The cells were differentiated into neutrophils by GGA stimulation like retinoic acid stimulation. In the case of cells stimulated with 2,3-diGGA, neutrophils were not detected, but the formation of lipid droplets was induced. On the other hand, when the cells were cultured in the presence of 0.1% FBS instead of 10% FBS, apoptotic cells were induced not only by GGA stimulation but also with 2,3-diGGA. In the latter case, when the cells were cultured in the co-presence of a caspase-3 inhibitor (Ac-DMQD-CHO), the lipid droplets formation was observed in the cells. These results suggest that GGA and 2,3-diGGA are extremely different from each other with respect to their effects on HL-60 cells.
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PMID:Formation of lipid droplets induced by 2,3-dihydrogeranylgeranoic acid distinct from geranylgeranoic acid. 1806 7

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