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)

Previously we showed that teratogen-induced cell death in mouse embryos is apoptotic in nature, i.e., involves the release of cytochrome c from mitochondria and the subsequent activation of caspase-3, cleavage of poly (ADP-ribose) polymerase (PARP), and internucleosomal DNA fragmentation. Herein we show that hyperthermia, 4-hydroperoxycyclophosphamide, and staurosporine also activate caspase-9, the apical caspase in the mitochondrial apoptotic pathway. Activation of procaspase-9 is associated with the cleavage of this proenzyme and the generation of two forms of the large subunit, primarily a 39-kDa subunit (p39) but also a lesser amount of a 37-kDa subunit (p37). We also present data that support the idea that the teratogen-induced formation of the p37 subunit in vivo occurs by the cytochrome c-mediated processing of procaspase-9, whereas the p39 subunit is formed by an amplification loop involving caspase-3. We also previously showed that the release of cytochrome c, activation of caspase-3, cleavage of PARP, and DNA fragmentation are blocked in cells of the developing heart, which are resistant to teratogen-induced cell death. We now show that this block in the mitochondrial apoptotic pathway in heart cells extends to the activation of procaspase-9. Thus, our cumulative data indicate that hyperthermia, 4-hydroperoxycyclophosphamide, and staurosporine induce cell death in Day 9 mouse embryos by activating the mitochondrial apoptotic pathway. In addition, our data suggest that cells of the Day 9 mouse embryo that are resistant to teratogen-induced cell death possess multiple mechanisms for inhibiting the mitochondrial apoptotic pathway after a teratogenic exposure.
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PMID:Teratogen-induced activation of caspase-9 and the mitochondrial apoptotic pathway in early postimplantation mouse embryos. 1205 98

Preeclampsia is a severe disorder of human pregnancy characterized by generalized activation of maternal endothelial cells. Oxidative stress of the placenta is considered a key intermediary step, precipitating deportation of apoptotic fragments into the maternal circulation, but the cause remains unknown. We hypothesize that intermittent placental perfusion, secondary to deficient trophoblast invasion of the endometrial arteries, leads to an ischemia-reperfusion-type insult. We therefore tested whether hypoxia-reoxygenation (H/R) in vitro stimulates apoptosis in human placental tissues compared with controls kept hypoxic or normoxic throughout. After H/R, release of cytochrome c from mitochondria was significantly increased and was associated with intense immunolabeling for active caspase 3 in the syncytiotrophoblast and fetal endothelial cells. There was also increased labeling of syncytiotrophoblastic nuclei for cleaved poly (ADP-ribose) polymerase (PARP), and higher cytosolic concentrations of cleaved PARP fragment were detected by Western blot. Syncytiotrophoblastic nuclei displayed increased chromatin condensation, and a significantly greater percentage was TUNEL positive. These changes were accompanied by increased lactate dehydrogenase release into the medium. Preadministration of the free radical scavenger, desferrioxamine, reduced cytochrome c release and the TUNEL-positive index, suggesting generation of hydroxyl radicals mediates these processes. By contrast, hypoxia alone caused a smaller increase in the TUNEL-positive index, and the majority of syncytiotrophoblastic nuclei displayed karyolysis, whereas normoxic controls remained euchromatic. We conclude that H/R stimulates apoptotic changes within the syncytiotrophoblast, whereas hypoxia principally induces necrosis. The quality of placental perfusion may therefore be a more important factor in the pathophysiology of preeclampsia than the absolute quantity.
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PMID:Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. 1208 65

Neuronal apoptosis is one of the pathological features of Alzheimer's disease (AD). Morphological pathology reveals that neuronal apoptosis is associated with senile plaques containing amyloid-beta peptide (Abeta) in AD brains. Reactive oxygen species (ROS) has been proposed to be involved in the apoptotic mechanism of Abeta-mediated neurotoxicity. In the present study, using a rat pheochromocytoma (PC12) cell line, we investigated the effect of Pycnogenol (PYC), a potent antioxidant and ROS scavenger, on Abeta(25-35)-induced apoptosis and ROS generation. We used vitamin E, a known antioxidant agent, to verify the effect of PYC. Abeta(25-35)-induced apoptosis in PC12 cells was demonstrated by: (1) a dose-dependent loss of cell viability; (2) a time- and dose-dependent increase in the apoptotic cells; (3) an induction of DNA fragmentation; and (4) an increase in caspase-3 activity and cleavage of poly (ADP-ribose) polymerase (PARP). Our data showed that a significant increase in ROS formation preceded apoptotic events after PC12 cells were exposed to Abeta(25-35). We further found that PYC not only suppressed the generation of ROS but also attenuated caspase-3 activation, DNA fragmentation, PARP cleavage, and eventually protected against Abeta-induced apoptosis. Vitamin E also suppressed cell death and caspase-3 activation induced by Abeta(25-35). Taken together, these results suggest that ROS may be involved in Abeta-induced apoptosis in PC12 cells. They further suggest that PYC can reduce apoptosis, possibly by decreasing free radical generation in PC12 cells.
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PMID:Pycnogenol protects neurons from amyloid-beta peptide-induced apoptosis. 1211 51

We studied the effect of momordin I, a compound purified from a plant, Ampelopsis japonica, on cell proliferation and induction of apoptosis in human promyelocytic leukemia (HL-60) cells. Momordin I was cytotoxic to HL-60 cells with an IC50 of 19.0 microg/ml. The antiproliferative effects of momordin I appear to be attributable to its induction of apoptotic cell death, as momordin I induced nuclear morphology changes and internucleosomal DNA fragmentation and it increased the proportion of hypodiploid cells. Momordin I treatment also gradually decreased the expression of.the anti-apoptotic protein Bcl-2, but increased the expression of the pro-apoptotic protein Bax. In addition, momordin I treatment increased the activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase. In this study we showed that momordin I induced apoptosis of HL-60 cells by reduction of the Bcl-2:Bax ratio and by activation of caspase-3. These results provide important information towards understanding the mechanism by which momordin I induces apoptosis.
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PMID:Induction of apoptosis by momordin I in promyelocytic leukemia (HL-60) cells. 1216 88

Using a binary co-transfection strategy of Ad/GT Bax and Ad/PGK-GV16, we have succeeded in inducing overexpression of Bax protein in three prostate cell lines (androgen-insensitive DU145 and PC3, and androgen-sensitive LNCaP). The expression of Bax protein by this system was sufficient to induce all three prostate lines to undergo apoptosis. The fact that DU145 cells which have a p53 mutation and are deficient in Bax, responded to this treatment, suggests that this effect is independent of these pathways. Initiation of the cleavage of Caspase-3 (CPP32/Yama/apopain) and PARP (poly (ADP-ribose) polymerase) by the introduction of Bax were confirmed by western blot analysis. Bcl-2 expression is relevant in the progression of prostate cancer and contributes to an androgen, apoptotic-resistant phenotype in the advanced stages. We examined stable Bcl-2 overexpressing DU145, PC3 and LNCaP cell lines as models of advanced prostate cancer. The adenoviral co-transfection system induced Bax protein expression and apoptosis even in these Bcl-2 transfected cell lines. Taken together, our results suggest that this Bax expression system might represent a useful gene therapy strategy when applied to the treatment of prostate cancer and its efficacy would be independent of the Bcl-2 status and androgen sensitivity of these cancers.
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PMID:A recombinant adenovirus expressing wild-type Bax induces apoptosis in prostate cancer cells independently of their Bcl-2 status and androgen sensitivity. 1217 Jul 76

Nutrient deprivation has been shown to cause cancer cell death. To exploit nutrient deprivation as anti-cancer therapy, we investigated the effects of the anti-metabolite 2-deoxy-D-glucose on breast cancer cells in vitro. This compound has been shown to inhibit glucose metabolism. Treatment of human breast cancer cell lines with 2-deoxy-D-glucose results in cessation of cell growth in a dose dependent manner. Cell viability as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide conversion assay and clonogenic survival are decreased with 2-deoxy-D-glucose treatment indicating that 2-deoxy-D-glucose causes breast cancer cell death. The cell death induced by 2-deoxy-D-glucose was found to be due to apoptosis as demonstrated by induction of caspase 3 activity and cleavage of poly (ADP-ribose) polymerase. Breast cancer cells treated with 2-deoxy-D-glucose express higher levels of Glut1 transporter protein as measured by Western blot analysis and have increased glucose uptake compared to non-treated breast cancer cells. From these results we conclude that 2-deoxy-D-glucose treatment causes death in human breast cancer cell lines by the activation of the apoptotic pathway. Our data suggest that breast cancer cells treated with 2-deoxy-D-glucose accelerate their own demise by initially expressing high levels of glucose transporter protein, which allows increased uptake of 2-deoxy-D-glucose, and subsequent induction of cell death. These data support the targeting of glucose metabolism as a site for chemotherapeutic intervention by agents such as 2-deoxy-D-glucose.
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PMID:Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death. 1223 67

To identify genes involved in cervical carcinogenesis, the mRNA differential display method was used. A 220-bp cDNA fragment called CA11 was present in normal cervical tissue but not in primary cervical cancer tissue or cervical cancer cell lines. CA11 exhibited 98% homology with the recorded human secreted frizzled-related protein (hsFRP) sequence. A dominant hsFRP mRNA transcript of approximately 4.6 kb was present in three normal cervical tissues examined. Expression of the transcript was nearly absent from three cervical cancer tissues and from five human cervical cancer-derived cell lines. Results from in situ hybridization showed that the hsFRP transcript was confined to the normal cervical epithelial layer. When hsFRP-transfected HeLa and CUMC-6 cervical cancer cells were cultured in serum-free medium, most of the cells died within 8 days. This effect is associated with the apoptotic process. The caspase-3 inhibitor 1, Ac-DEVD-CHO, blocked hsFRP-induced apoptotic cell death. Additionally, cleavage of poly (ADP-ribose) polymerase in hsFRP-transfected cells was confirmed by colorimetric assay. These results indicate that the hsFRP gene probably functions as a tumor suppressor in normal cervical epithelium and down-regulation of hsFRP contributes to development of cervical cancer.
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PMID:Human secreted frizzled-related protein is down-regulated and induces apoptosis in human cervical cancer. 1241 93

It has been reported that inositol hexakisphosphate (InsP(6), phytic acid), a natural product, has an anticancer role. However, there is inadequate information regarding the mechanism by which InsP(6) exerts anticancer actions, and the effect requires relatively high concentration of the agent, both of which hinders the usage of InsP(6) as an anticancer drug. In the present study, we investigated the mechanism by which InsP(6) acts as an anticancer agent, and tried to reduce the concentration of effective InsP(6). Treatment of HeLa cells with InsP(6) at 1 mM induced apoptosis, as assessed by counting the cell number, and by Hoechst and TUNEL staining. This is probably mediated by intracellular InsP(6) itself and/or the dephosphorylated forms of metabolized InsP(6), because incubation of HeLa cells with [(3)H]InsP(6) produces dephosphorylated forms such as InsP(4) and InsP(5). Induction of apoptosis by InsP(6) was examined in two ways: inhibition of cell survival signaling and direct induction of apoptosis. Treatment of HeLa cells with tumor necrosis factor (TNF) or insulin stimulated the Akt-nuclear factor kappaB (NFkappaB) pathway, a cell survival signal, which involves the phosphorylation of Akt and IkappaB, nuclear translocation of NFkappaB and NFkappaB-luciferase transcription activity. InsP(6) blocked all these cellular events, but phosphatidylinositol 3-kinase activity was not affected. As well as inhibiting the Akt-NFkappaB pathway, InsP(6) itself caused mitochondrial permeabilization, followed by cytochrome c release, which later caused activation of the apoptotic machinery, caspase 9, caspase 3 and poly (ADP-ribose) polymerase. When InsP(6) was applied together with histone, the effective concentration to induce apoptosis was approximately 10-fold lower. These results revealed that extracellularly applied InsP(6) directly activates the apoptotic machinery as well as inhibits the cell survival signaling, probably by the intracellular delivery followed by a dephosphorylation.
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PMID:Inositol hexakisphosphate blocks tumor cell growth by activating apoptotic machinery as well as by inhibiting the Akt/NFkappaB-mediated cell survival pathway. 1250 26

Apoptotic death is a physiological process with regulatory mechanisms that are under the control of different molecules such as caspases. These are classified as initiators, such as caspases-8 and -9, and effectors, such as caspases-3 and -7. The participation of caspase-2 in the effector phase of apoptosis has been commonly observed in many cell types; however, it is able to act as an initiator caspase, depending on the apoptotic stimulus. Cerebellar granule cells (CGCs) undergo apoptosis when they are transferred from high potassium (K25) to low potassium (K5); this process seems to be mediated by caspase-3 activation. Staurosporine (STS), a full strength inhibitor of kinase proteins, also induces apoptosis in these cells. To characterize the caspase cascade induced by two stimuli in the same cell type we studied the activation of different caspases in CGCs treated with STS or K5. We found that both K5 and STS induce the activation of caspase-3. This result was confirmed by the proteolytic cleavage of poly (ADP-ribose) polymerase (PARP), an endogenous caspase-3 substrate. Caspase-2 was activated preferentially by STS, which showed a temporal course suggesting that this caspase was induced before caspase-3. The initiator caspase-9 was also activated by both K5 and STS, as well as cytochrome-c release. The results obtained in this study suggest that STS and K5 induced different activation caspase pathways for apoptotic cell death of CGCs.
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PMID:Caspase activation pathways induced by staurosporine and low potassium: role of caspase-2. 1252 27

Apoptotic cell death has been proposed to play a role in the neuronal loss observed following traumatic injury in the CNS and PNS. The present study uses an in vitro tissue culture model to investigate whether free fatty acids (FFAs), at concentrations comparable to those found following traumatic brain injury, trigger cell death. Nerve growth factor (NGF)-differentiated PC12 cells exposed to oleic and arachidonic acids (2 : 1 ratio FFA/BSA) showed normal cell survival. However, when cells were exposed to stearic and palmitic acids, there was a dramatic loss of cell viability after 24 h of treatment. The cell death induced by stearic acid and palmitic acid was apoptotic as assessed by morphological analysis, and activation of caspase-8 and caspase-3-like activities. Western blotting showed that differentiated PC12 cells exposed to stearic and palmitic acids exhibited the signature apoptotic cleavage fragment of poly (ADP-ribose) polymerase (PARP). Interestingly, blockade of caspase activities with the pan-caspase inhibitor z-VAD-fmk failed to prevent the cell death observed induced by palmitic or stearic acid. RT-PCR and RNA blot experiments showed an up-regulation of the Fas receptor and ligand mRNA. These findings are consistent with our hypothesis that FFAs may play a role in the cell death associated with trauma in the CNS and PNS.
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PMID:Palmitic and stearic fatty acids induce caspase-dependent and -independent cell death in nerve growth factor differentiated PC12 cells. 1256 10


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