Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study two monocytic leukemia cell lines, U937 and THP-1 cells, were used to investigate the anti-proliferation effects caused by ponicidin. Cell viability was measured by an MTT assay. Cell apoptosis was assessed by flow cytometry as well as DNA fragmentation analysis. Cell morphology was observed using an inverted microscope and Hoechst 33258 staining. RT-PCR and Western blot analysis were used to detect survivin as well as Bax and Bcl-2 expressions after the cells were treated with different concentrations of ponicidin. The results revealed that ponicidin could inhibit the growth of U937 and THP-1 cells significantly by induction of apoptosis. The suppression was in both time- and dose-dependent manner. Marked morphological changes of cell apoptosis were observed clearly after the cells were treated with ponicidin for 48 approximately 72 h. RT-PCR and Western blot analysis demonstrated that both survivin and Bcl-2 expressions were down-regulated remarkably while Bax expression remained constant before and after apoptosis occurred. We therefore conclude that ponicidin has significant anti-proliferation effects by inducing apoptosis on leukemia cells in vitro, downregulation of survivin as well as Bcl-2 expressions may be the important apoptosis inducing mechanisms. The results suggest that ponicidin may serve as potential therapeutic agent for leukemia.
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PMID:Ponicidin inhibits monocytic leukemia cell growth by induction of apoptosis. 1933 74

Corticotropin-releasing factor (CRF) exerts proinflammatory effects in peripheral tissues, whereas the intracellular pathways mediating these effects have not been completely characterized yet. We have previously shown that CRF induces nuclear factor-kappaB DNA-binding activity in mouse and human leukocytes. Here we demonstrate that in the human monocytic THP-1 cells, CRF activates the phosphatidylinositol 3-kinase (PI3K)/Akt and ERK1/2 pathways. These effects of CRF are mediated by corticotropin-releasing factor receptor 2 (CRF2), as suggested by their abolishment after treatment with the specific CRF2 antagonist, astressin 2B. The CRF-mediated PI3K/Akt activation induces cell survival as suggested by the stimulation of the antiapoptotic factor Bcl-2. ERK1/2 activation results in up-regulation of IL-8 expression, an effect inhibited by the CRF-induced activation of PI3K/Akt. These studies demonstrate novel effects of CRF in human monocytes mediated by the activation of PI3K/Akt. Moreover, they reveal pathway-specific effects of the CRF/CRF2 system in chemokine activation and cell survival that may be of importance for the development of novel therapeutics for inflammatory diseases.
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PMID:Activation of phosphatidylinositol 3-kinase/protein kinase B by corticotropin-releasing factor in human monocytes. 1962 76

Betuletol 3-methyl ether (BME) is a natural phenylbenzo-gamma-pyrone that inhibits cell proliferation in human tumor cell lines and induces apoptotic cell death in HL-60 cells. Here we show that BME displays strong cytotoxic properties in several human leukemia cell lines (U937, K-562, THP-1, Jurkat, and Molt-3) and in cells that over-express two anti-apoptotic proteins, namely Bcl-2 and Bcl-x(L). BME arrested HL-60 cells at G(2)-M phase of the cell cycle, which was associated with the accumulation of cyclin B1 and p21(Cip1). Fluorescence microscopy experiments suggest that BME blocked the cell cycle in mitosis. The in vivo tubulin polymerization assay shows that BME inhibits tubulin polymerization and causes similar changes of cellular microtubule network as colchicine. Our results demonstrate that BME-induced cell death is (i) triggered in human myeloid leukemia cell that over-express Bcl-2 and Bcl-x(L), and (ii) associated with loss of inner mitochondrial membrane potential (DeltaPsim) and an increase in reactive oxygen species (ROS). Although ROS increased in response to BME, this did not seem to play a pivotal role in the apoptotic process since the anti-oxidant trolox was unable to provide cell protection. The treatment of HL-60 cells with BME induces the activation of mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinases, p38 mitogen-activated protein kinases and extracellular signal-regulated kinases (ERK)1/2 and stimulates the acid sphingomyelinase with concomitant ceramide generation. The findings of this study suggest that BME could be useful in the development of novel anticancer agents.
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PMID:Betuletol 3-methyl ether induces G(2)-M phase arrest and activates the sphingomyelin and MAPK pathways in human leukemia cells. 1967 4

Shiga toxins (Stxs), which are proteins expressed by the enteric pathogens Shigella dysenteriae serotype 1 and some serotypes of Escherichia coli, are potent protein synthesis inhibitors. Stx-producing organisms cause bloody diarrhea with the potential to progress to acute renal failure and central nervous system complications. Studies using animal models of these diseases have shown that Stxs are major virulence factors, and purified toxins have been shown to be capable of killing many types of cells in vitro. We showed that Stx type 1 (Stx1) rapidly induced apoptosis in undifferentiated, monocytic THP-1 cells through a mechanism involving the endoplasmic reticulum (ER) stress response. Rapid apoptosis correlated with increased expression of C/EBP homologous protein (CHOP), TRAIL, and DR5, while expression of the antiapoptotic factor Bcl-2 was downregulated. Stx1 treatment of differentiated, macrophage-like THP-1 cells was associated with cytokine production and delayed apoptosis. The mechanisms contributing to cell maturation-dependent differences in responses to Stx1 are unknown. We show here that in macrophage-like cells, Stx1 activated the proximal ER stress sensors RNA-dependent protein kinase-like ER kinase and inositol-requiring ER signal kinase 1alpha but did not activate activating transcription factor 6. Proapoptotic signaling pathways mediated by CHOP and by Bax and Bak were activated by Stx1. However, the toxin also activated prosurvival signaling through increased expression, mitochondrial translocation, and alternative phosphorylation of Bcl-2.
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PMID:Bcl-2 regulates the onset of shiga toxin 1-induced apoptosis in THP-1 cells. 1975 28

Steroidogenic acute regulatory protein (StAR) plays an important role in the maintenance of intracellular lipid homeostasis. Macrophages are the key cellular player in the pathophysiology of atherosclerosis. Imbalance of macrophage lipid homeostasis causes cellular apoptosis, which is the key process in the initiation of atherosclerosis. The present study has investigated the effects of StAR in the apoptotic process of human THP-1 derived macrophages induced by serum withdrawal or Ox-LDL. Overexpression of StAR significantly decreased the number of apoptotic macrophages by decreasing the expression of pro-apoptotic genes Caspase-3 and Bax mRNA and protein levels, as well as through increasing expression of anti-apoptotic gene Bcl-2 mRNA and protein levels in the absence and presence of Ox-LDL. The results indicate that StAR plays an important role in macrophage and foam cell apoptotic processing, which may provide a potential method for preventing atherosclerosis.
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PMID:Mitochondrial cholesterol transporter, StAR, inhibits human THP-1 monocyte-derived macrophage apoptosis. 1994 56

The analgesic agent levo-tetrahydropalmatine (l-THP) was reported to be associated with acute or chronic hepatitis in clinical practice. We found that l-THP can induce apoptosis in the hepatocytes of BALB/c mice and human normal liver L-02 (L-02) cells. Several key molecules, including caspase-3, Bcl-2, BAD and Bax, were modulated by l-THP treatment. A novel high-throughput proteomic approach based on 2D-nano-LC-MS/MS was applied to simultaneously evaluate the alterations of global protein expression involved in the response of l-THP treatment in L-02 cells. A total of 156 deregulated proteins were identified, among which 12 proteins play regulatory or constitutive roles in the apoptosis pathways. Further analyses of two proteins (mTOR and MEK2) by Western Blots confirmed that these proteins were expressed at lower levels in l-THP-treated L-02 cells compared with those of control. The current study provided detailed evidence to support that l-THP is capable of inducing apoptosis in mammalian liver cells and improve the understanding of mechanisms of l-THP-induced hepatotoxicity.
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PMID:Shotgun approach based comparative proteomic analysis of levo-tetrahydropalmatine-induced apoptosis in hepatocytes. 2010 41

Human macrophages express oestrogen receptors and are therefore competent to respond to the hormone present in their microenvironment, which is implicated in sexual dimorphism observed in several immune and autoimmune phenomena. An earlier study from this laboratory demonstrated 17beta-oestradiol (E2) induced apoptosis in macrophages derived from human peripheral blood monocytes and THP-1 acute monocytic leukaemia cell line when Bcl-2 was down-regulated; however, the involvement of E2 receptor subtypes in the modulation of death pathways in these cells remain unknown. Using macrophages derived from THP-1 human acute monocytic leukaemia cells as a model, we demonstrate that plasma membrane associated oestrogen receptor (ER) -alpha participate in E2 induced Bcl-2 increase, through activation of the mitogen activated protein kinase (MAPK) pathway whereas cytosolic ER-beta transmits signals for the pro-apoptotic event of Bax translocation. The mechanistic basis of Bax translocation comprised of ER-beta mediated increase in intracellular pH, facilitated by activation of the Na(+)-H(+) exchanger. Intracellular alkalinization accompanied by concomitant Bcl-2 increase and Bax migration does not cause cellular apoptosis; however, siRNA mediated down-regulation of ER-alpha during E2 exposure leads to inhibition of Bcl-2 increase and consequently apoptosis due to the unopposed action of mitochondrial Bax. In summary, this study underscores the importance of integrative signalling modality from multiple oestrogen receptor pools in modulating oestrogen effects on human monocyte-derived macrophage apoptotic signalling pathway, which opens new vistas to explore the use of selective oestrogen receptor modulators in apoptosis-based therapies.
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PMID:Oestrogen modulates human macrophage apoptosis via differential signalling through oestrogen receptor-alpha and beta. 2014 15

Co(III)-cyclen complexes are known to cause DNA strand breaks by hydrolytically cleaving the phosphodiester backbone via a mechanism that does not require oxidation. Here, we report the first cytotoxicity study of [Co(III)(cyclen)Cl(2)]Cl (2), the parental example of this class of agent, which reveals that (2) is selectively toxic towards CCRF-CEM (IC(50)=32+/-10 microM), THP-1 (IC(50)=110+/-40 microM), and HL-60 (IC(50)=70+/-35 microM) human leukaemia cells, compared to human skin and lung fibroblasts (IC(50)>10 mM). Investigations of its effect on CCRF-CEM cells show it kills by apoptosis which was characterised by microscopy, flow cytometry, and in vitro NMR experiments. The latter involved measurement of the ratio of methylene and methyl (1)H resonances at 1.3 and 0.9 ppm, respectively, associated with the externalisation of membrane bound phosphatidyl serine. The NMR data indicate increasing lactate production during apoptosis, which implies involvement of the intrinsic mitochondrial pathway, a notion supported by down-regulation of Bcl-2 and up-regulation of Bax levels as detected by Western blotting.
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PMID:[Co(III)(cyclen)Cl2]Cl is selectively cytotoxic to human leukaemia cells. 2038 17

Up-regulation of telomerase activity is associated with immortalization and unlimited cell division in most cancer cells. Therefore, telomerase represents a particularly attractive target for anticancer therapy. Recent reports have suggested that beta-lapachone (LAPA), the product of the South American Tabebuia avellanedae tree, inhibits growth of tumor cells. However, the underlying relationship between telomerase activity and apoptosis in response to LAPA exposure in leukemia cells remains poorly understood. In this study, we confirmed that LAPA treatment induces direct cytotoxicity in human leukemia cells (U937, K562, HL60, and THP-1) through activation of caspase-3 and subsequent cleavage of poly(ADP-ribose) polymerase. The observed induction of cell death was associated with decreased telomerase activity, which was ascribed to down-regulation of telomerase reverse transcriptase. Additionally, overexpression of anti-apoptotic Bcl-2 could not overcome the induction of apoptosis or the decreased telomerase activity in response to treatment of U937 cells with LAPA. We conclude that LAPA has a direct cytotoxic effect and the loss of telomerase activity in leukemia cells.
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PMID:Beta-lapachone (LAPA) decreases cell viability and telomerase activity in leukemia cells: suppression of telomerase activity by LAPA. 2043 29

Shiga toxins (Stxs) induce apoptosis via activation of the intrinsic and extrinsic pathways in many cell types. Toxin-mediated activation of the endoplasmic reticulum (ER) stress response was shown to be instrumental in initiating apoptosis in THP-1 myeloid leukemia cells. THP-1 cells responded to Shiga toxin type 1 (Stx1) in a cell maturation-dependent manner, undergoing rapid apoptosis in the undifferentiated state but reduced and delayed apoptosis in differentiated cells. The onset of apoptosis was associated with calpain activation and changes in expression of C/EBP homologous protein (CHOP), Bcl-2 family members, and death receptor 5 (DR5). Ligation of DR5 by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) activates the extrinsic pathway of apoptosis. We show here that expression of TRAIL and DR5 is increased by Stx1 treatment. Addition of exogenous TRAIL enhances, and anti-TRAIL antibodies inhibit, Stx1-induced apoptosis of THP-1 cells. Silencing of CHOP or DR5 expression selectively prevented caspase activation, loss of mitochondrial membrane potential, and Stx1-induced apoptosis of macrophage-like THP-1 cells. In contrast, the rapid kinetics of apoptosis induction in monocytic THP-1 cells correlated with rates of calpain cleavage. The results suggest that CHOP-DR5 signaling and calpain activation differentially contribute to cell maturation-dependent Stx1-induced apoptosis. Inhibition of these signaling pathways may protect cells from Stx cytotoxicity.
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PMID:Signaling through C/EBP homologous protein and death receptor 5 and calpain activation differentially regulate THP-1 cell maturation-dependent apoptosis induced by Shiga toxin type 1. 2051 24


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