Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myelodysplastic syndromes (MDS) constitute a preneoplastic condition in which potentially malignant cancer stem cells continuously die during differentiation. This MDS-associated cell death often involves caspase-3 activation, yet can also occur without caspase activation, for instance in differentiating megakaryocytes (MK). We investigated, the mechanisms through which MK from MDS patients undergo premature cell death. While polyploid, mature MK from healthy subjects or MDS patients manifested caspase-3 activation during terminal differentiation, freshly isolated, immature MK from MDS died without caspase-3 activation. Similarly, purified bone marrow CD34(+) cells from MDS patients that were driven into MK differentiation in vitro died without caspase-3 activation at an immature stage, before polyploidization. The premature death of MDS MK was accompanied by the mitochondrial release of cytochrome c, Smac/DIABLO and endonuclease G, a caspase-independent death effector, as well loss of the mitochondrial membrane potential and plasma membrane phosphatidylserine exposure before definitive loss of viability. Thus, a stereotyped pattern of mitochondrial alterations accompanies differentiation-associated MK death in MDS.
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PMID:Differentiating megakaryocytes in myelodysplastic syndromes succumb to mitochondrial derangement without caspase activation. 1724 43

Hypoxia is an often seen problem resulting from conditions such as ischemia, hemorrhage, stroke, premature birth, and other cardiovascular difficulties. To find useful remedies that are capable of ameliorating its casualty is an essential effort. Although the underlying mechanisms of the hypoxia-induce injury and cell death are still not fully understood, it has been shown that hypoxia induces nitric oxide (NO) overproduction and inducible nitric oxide synthase (iNOS) overexpression that play important roles in producing injury including increases in polymorphonuclear neutrophils (PMN) infiltration to injured tissues and leukotriene B4 (LTB4) generation. Moreover, it has been evident that transcription factors responsible for iNOS expression are also altered by hypoxia. Hypoxia also increases intracellular Ca2+ concentration, tumor necrosis factor-alpha, lipid peroxidation, prostaglandin E2 production, activity of caspase-3 and -9, and release of cytochrome c from mitochondria, apoptosis inducible factor, and endonuclease G. However, it has been shown that downregulation of iNOS can limit cell injury caused by hypoxia. In our laboratory, we have found that treatment with either iNOS inhibitors or iNOS siRNA inhibits iNOS expression, reduces lipid peroxidation, apoptosome formation, and cellular caspase-3 activity, preserves cellular ATP levels, and increases cell survival. Therefore, iNOS inhibition may be a novel mechanism for protection from hypoxia-induced injury and cell death.
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PMID:Biology of hypoxia. 1729 30

Although it has been previously reported that bee venom (BV) can induce apoptosis in many cancer cell lines, there is no information on the effect of BV on human cervical cancer cells and its molecular mechanisms of action are not fully elucidated. In this study, the possible mechanisms of apoptosis by which BV acts on human cervical cancer Ca Ski cells were investigated. BV induced morphological changes and decreased the percentage of viable Ca Ski cells in a dose- and time-dependent manner. Flow cytometric analysis demonstrated that BV induced the production of reactive oxygen species, increased the level of cytoplasmic Ca2+, reduced mitochondrial membrane potential which led to cytochrome c release, and promoted the activation of caspase-3 which then led to apoptosis. BV also induced an increase in the levels of Fas, p53, p21 and Bax, but a decrease in the level of Bcl-2. The activities of both caspase-8 and caspase-9 were enhanced by BV, promoting caspase-3 activation, leading to DNA fragmentation. Based on the DNA fragmentation and DAPI staining, BV-induced apoptosis was mitochondrial-dependent and caspase-dependent. BV also promoted the expression of AIF and Endo G in the Ca Ski cells. Both AIF and Endo G proteins were released from the mitochondria, and then induced apoptosis which was not through activation of caspase. In conclusion, our data demonstrated that BV-induced apoptosis occurs via a Fas receptor pathway involving mitochondrial-dependent pathways and is closely related to the level of cytoplasmic Ca2+ in Ca Ski cells.
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PMID:Bee venom induced cell cycle arrest and apoptosis in human cervical epidermoid carcinoma Ca Ski cells. 1850 26

Gypenosides (Gyp), a component of Gynostemma pentaphyllum Makino, was selected for examining the effects on the cell viability, cell cycle and induction of apoptosis in human tongue cancer SCC-4 cells. Gyp induced cytotoxicity (decreased the percentage of viable cells) in SCC-4 cells appeared to be associated with induction of cell cycle arrest (G0/G1 arrest), apoptotic cell death based on Gyp induced morphological changes and DNA fragmentation and increased the sub-G1 group in examined SCC-4 cells. The production of reactive oxygen species and Ca(2+) and the depolarization of mitochondrial membrane potential were observed, dose- and time-dependently, after treatment of SCC-4 cells with various concentrations of Gyp. Gyp inhibited the levels of the anti-apoptotic proteins Bcl-2 and Bcl-xl, but promoted the levels of the pro-apoptotic protein Bax. Western blotting showed the releases of cytochrome c and Endo G and both were also confirmed by confocal laser microscopic systems. The GADD153 moved to nuclei (nuclear translocation). In conclusion, Gyp induced ER stress and production of reactive oxygen species and Ca(2+), change the ratio of Bcl-2 and Bax, followed by the dysfunction of mitochondria, caused cytochrome c release, activation of caspase-3 before leading to apoptosis. These results provide information towards an understanding of the mechanisms by which Gyp induces cell cycle arrest and apoptosis in human tongue cancer cells.
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PMID:Gypenosides induced G0/G1 arrest via CHk2 and apoptosis through endoplasmic reticulum stress and mitochondria-dependent pathways in human tongue cancer SCC-4 cells. 1867 53

To investigate the possibility that tumor cells undergoing linearly patterned programmed cell necrosis (LPPCN) establish a spatial foundation for vasculogenic mimicry (VM) and to reveal that hypoxia influences LPPCN formation as well as Endo G and DNase 1 expression, 78 C57 mice were divided evenly into two groups and engrafted with B16 melanoma. Starting 9 days after inoculation, subgroups of mice were killed every 2 days. LPPCN and the tumor blood supply vessel types were counted and Endo G and DNase 1 mRNA expression were measured. Additionally, 124 cases of human melanoma samples were collected to assess the clinical significance of LPPCN and VM. The data revealed that regions of LPPCN were positive for caspase-3, caspase-9 and Bax, and negative for TUNEL staining. Electron microscopy images indicated that these cells took on the morphologic changes of necrosis. There was more DNase I mRNA expression in the hypoxic group than in the control group (P<0.05) in vitro, and the expression of Endo G mRNA in the hypoxic groups was significantly higher than that in the control groups both in vitro and in vivo (P<0.05). VM and LPPCN cell numbers in the ischemic group were higher than those in the control group in the early stage of tumor growth. Finally, the survival time for patients whose samples showed LPPCN and VM was significantly shorter than that of patients with one or neither of those factors. We speculated that under hypoxic conditions, some melanoma cells might undergo LPPCN, thus providing a spatial foundation for VM channel formation.
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PMID:Hypoxia influences linearly patterned programmed cell necrosis and tumor blood supply patterns formation in melanoma. 1929 5

Astrocytes, the most abundant glial cell population in the central nervous system (CNS), play physiological roles in neuronal activities. Oxidative insult induced by the injury to the CNS causes neural cell death through extrinsic and intrinsic pathways. This study reports that reactive oxygen species (ROS) generated by exposure to the strong oxidizing agent, hexavalent chromium (Cr(VI)) as a chemical-induced oxidative stress model, caused astrocytes to undergo an apoptosis-like cell death through a caspase-3-independent mechanism. Although activating protein-1 (AP-1) and NF-kappaB were activated in Cr(VI)-primed astrocytes, the inhibition of their activity failed to increase astrocytic cell survival. The results further indicated that the reduction in mitochondrial membrane potential (MMP) was accompanied by an increase in the levels of ROS in Cr(VI)-primed astrocytes. Moreover, pretreatment of astrocytes with N-acetylcysteine (NAC), the potent ROS scavenger, attenuated ROS production and MMP loss in Cr(VI)-primed astrocytes, and significantly increased the survival of astrocytes, implying that the elevated ROS disrupted the mitochondrial function to result in the reduction of astrocytic cell viability. In addition, the nuclear expression of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) was observed in Cr(VI)-primed astrocytes. Taken together, evidence shows that astrocytic cell death occurs by ROS-induced oxidative insult through a caspase-3-independent apoptotic mechanism involving the loss of MMP and an increase in the nuclear levels of mitochondrial pro-apoptosis proteins (AIF/EndoG). This mitochondria-mediated but caspase-3-independent apoptotic pathway may be involved in oxidative stress-induced astrocytic cell death in the injured CNS.
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PMID:Reactive oxygen species-induced cell death of rat primary astrocytes through mitochondria-mediated mechanism. 1945 61

Novel 2-phenyl-4-quinolone compounds have potent cytotoxic effects on different human cancer cell lines. In this study, we examined anticancer activity and mechanisms of 20-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (CHM-1) in human osterogenic sarcoma U-2 OS cells. CHM-1-induced apoptosis was determined by flow cytometric analysis, DAPI staining, Comet assay, and caspase inhibitors. CHM-1-inhibited cell migration and invasion was assessed by a wound healing assay, gelatin zymography, and a Transwell assay. The mechanisms of CHM-1 effects on apoptosis and metastasis signaling pathways were studied using Western blotting and gene expression. CHM-1 induced G2/M arrest and apoptosis at an IC(50) (3 microM) in U-2 OS cells and caspase-3, -8, and -9 were activated. Caspase inhibitors increased cell viability after exposure to CHM-1. CHM-1-induced apoptosis was associated with enhanced ROS generation, DNA damage, decreased DeltaPsi(m) levels, and promotion of mitochondrial cytochrome c release. CHM-1 stimulated mRNA expression of caspase-3, -8, and -9, AIF, and Endo G. In addition, CHM-1 inhibited cell metastasis at a low concentration (<3 microM). CHM-1 inhibited the cell metastasis through the inhibition of MMP-2, -7, and -9. CHM-1 also decreased the levels of MAPK signaling pathways before leading to the inhibition of MMPs. In summary, CHM-1 is a potent inducer of apoptosis, which plays a role in the anticancer activity of CHM-1.
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PMID:Novel quinolone CHM-1 induces apoptosis and inhibits metastasis in a human osterogenic sarcoma cell line. 1955 55

To characterize neuronal death, primary cortical neurons (C57/Black 6 J mice) were exposed to hydrogen peroxide (H2O2) and staurosporine. Both caused cell shrinkage, nuclear condensation, DNA fragmentation and loss of plasma membrane integrity. Neither treatment induced caspase-7 activity, but caspase-3 was activated by staurosporine but not H2O2. Each treatment caused redistribution from mitochondria of both endonuclease G (Endo G) and cytochrome c. Neurons knocked down for Endo G expression using siRNA showed reduction in both nuclear condensation and DNA fragmentation after treatment with H2O2, but not staurosporine. Endo G suppression protected cells against H2O2-induced cell death, while staurosporine-induced death was merely delayed. We conclude that staurosporine induces apoptosis in these neurons, but severe oxidative stress leads to Endo G-dependent death, in the absence of caspase activation (programmed cell death-type III). Therefore, oxidative stress triggers in neurons a form of necrosis that is a systematic cellular response subject to molecular regulation.
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PMID:Oxidative stress triggers neuronal caspase-independent death: endonuclease G involvement in programmed cell death-type III. 1958 70

We previously reported that 1-nitropyrene (1-NP) and 3-nitrofluoranthene (3-NF) elicited apoptotic cell death as well as non-apoptotic programmed cell deaths (PCDs) with paraptotic and necroptotic characteristics, respectively. In the present study, we have further confirmed and extended these findings. Flow cytometric analyses of 1-NP-exposed/3NF-exposed Hepa1c1c7 cells revealed that caspase-3 was only activated in the subpopulation of cells corresponding to that with classic apoptotic morphology. Immunocytochemical analysis indicated that leucocyte elastase inhibitor-derived DNaseII (LEI/L-DNaseII), apoptosis-inducing factor (AIF) and endonuclease G (EndoG) were more clearly translocated to the nucleus following 3-NF exposure than after 1-NP. These 3-NF-induced changes in AIF and EndoG translocation were reduced by necrostatin-1, an inhibitor of necroptotic cell death. Both compounds lead to accumulation of lipid droplets and induced DNA damage. Activation of checkpoint kinase (CHK) 1 and H2AX, but not ataxia telangiectasia mutated and CHK2, were observed. Furthermore, inhibition of p53 using pifithrin-alpha reduced the cell death induced by both compounds, suggesting a role of DNA damage/CHK1/p53 pathway in the death process. 1-NP-induced cell death was in addition characterized by increased oxidative damage and intracellular accumulation of Ca(2+). These findings further support the notion that 1-NP elicited apoptotic cell death and PCD with paraptotic characteristics, while 3-NF induced apoptosis and a PCD with necroptotic features.
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PMID:Signalling pathways involved in 1-nitropyrene (1-NP)-induced and 3-nitrofluoranthene (3-NF)-induced cell death in Hepa1c1c7 cells. 1970 35

Many phytochemicals have been recognized to have potential chemopreventive or chemotherapeutic efficacy in cancer treatment. In this study, we hypothesized that berberine would have anticancer activities in SCC-4 human tongue cancer cells. Results indicated that berberine reduced the viability of SCC-4 cells, which was initiated by the generation of reactive oxygen species, via an increase in cytosolic Ca(2+). Berberine-induced apoptosis was associated with a reduction of the mitochondrial membrane potential associated with changes in the Bax/Bcl-2 ratio, release of cytochrome c from mitochondria and activation of down stream caspase-3. Real-time PCR showed that berberine stimulated gene expression of caspase-8, -9 and -3, apoptosis-inducing factor and endonuclease G. The present study demonstrated that berberine-mediated apoptosis of SCC-4 cells is regulated by ROS, mitochondria, caspase-3-dependent and mitochondria-dependent pathways, suggesting that berberine may be considered for future studies as a promising therapeutic candidate for human tongue cancer.
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PMID:Berberine induced apoptosis via promoting the expression of caspase-8, -9 and -3, apoptosis-inducing factor and endonuclease G in SCC-4 human tongue squamous carcinoma cancer cells. 1984 52


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