Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several papers report that the colon is one of the tissues regulated by estrogen receptor (ER)beta. To better understand the physiological role of ERbeta in colonic tissue, we have compared morphology, proliferation, and differentiation of colonic epithelium in ERbeta-/- mice and WT littermates. BrdUrd labeling revealed that the number of proliferating cells was higher in ERbeta-/- mice and that the migration of labeled cells toward the luminal surface was faster in ERbeta-/- mice than in WT littermates. Additionally, in the absence of ERbeta, there was a decrease in apoptosis, which was measured by immunohistochemical staining of cleaved caspase-3. The state of differentiation of the colonic epithelial cells was studied by using epithelial markers. In ERbeta-/- mice, there was a significant decrease in the expression of the differentiation marker cytokeratin (CK)20 and in the cellular adhesion molecules alpha-catenin (an adherens junction protein) and plectin (a hemidesmosomal protein). These changes were also evident by electron microscopy as abnormalities in tight junctions and in the number and shape of desmosomes in ERbeta-/- mice. These findings suggest a role for ERbeta in the organization and architectural maintenance of the colon. Furthermore, our results indicate that the rapidly proliferating cells of the colonic epithelium in ERbeta-/- mice are lost by increased shedding and not by increased apoptosis. In this way, hyperproliferative cells that lack ERbeta do not form hyperplastic lesions and do not accumulate in the superficial epithelium.
 ...
PMID:Role of estrogen receptor beta in colonic epithelium. 1647 31

Agonists to A3 adenosine receptor (A3AR) have been reported to inhibit cell growth and/or induce apoptosis in various tumors. We tested the effect of a novel A3AR agonist generically known as LJ-529 in breast cancer cells. Anchorage-dependent cell growth and in vivo tumor growth were attenuated by LJ-529, independently of its estrogen receptor (ER) alpha status. In addition, apoptosis was induced as evidenced by the activation of caspase-3 and c-poly(ADP)ribose polymerase. Furthermore, the Wnt signaling pathway was down-regulated and p27(kip) was induced by LJ-529. In ER-positive cells, the expression of ER was down-regulated by LJ-529, which might have additionally contributed to attenuated cell proliferation. In ER-negative, c-ErbB2-overexpressing SK-BR-3 cells, the expression of c-ErbB2 and its downstream extracellular signal-regulated kinase pathway were down-regulated by LJ-529. However, such effect of LJ-529 acted independently of its receptor because no A3AR was detected by reverse transcription-PCR in all four cell lines tested. In conclusion, our novel findings open the possibility of LJ-529 as an effective therapeutic agent against both ER-positive and ER-negative breast cancers, particularly against the more aggressive ER-negative, c-ErbB2-overexpressing types.
 ...
PMID:The antitumor effect of LJ-529, a novel agonist to A3 adenosine receptor, in both estrogen receptor-positive and estrogen receptor-negative human breast cancers. 1654 83

Hepatocellular carcinoma (HCC), the major manifestation of primary liver cancer, is one of the most frequent and malignant cancers worldwide, especially in Taiwan. Estrogen receptors (ERs) have been reported to play either a proliferation- or apoptosis-enhancing role in the differentiation of cancers, including HCC. In a previous experiment, we showed that transient overexpressed estrogen receptor-alpha induced early stage HCC cell line Hep 3B cell apoptosis by increasing the hTNF-alpha gene expression in a ligand-independent manner. To further clarify if the apoptotic effect occurs in poorly differentiated HCC cell line, HA22T, and elucidate the roles of ERs and TNF-alpha, DNA fragmentation and caspase activity were measured in late stage HCC cell line, HA22T, by measuring the expression of hER-alpha and hER-beta using a Tetracycline-inducible system (Tet-on). Increased DNA fragmentation and caspase-3 activity were found in hERbeta-overexpressed HA22T cells treated with estrogen (10(-8) M) but not in hERalpha-overexpressed HA22T cells. Using RT-PCR/PCR and western blotting in HA22T cells, overexpressed hER-beta was also found to increase the expression of hTNF-alpha mRNA and induce hTNF-alpha-dependent luciferase activity in a ligand-dependent manner. Additionally, LPS treatment and hER-beta overexpression both enhance caspase-8 activities, whereas neither hER-beta nor E2 treatment affected caspase-9 activities. In addition, the overexpressed hER-beta plus E2 enhanced DNA fragmentation and caspase-8 activities were only partially reduced by anti-hTNF-alpha (0.1 ng/ml), which was possibly due to the involvement of P53 and TGF-beta. Taken together, our data indicates that overexpressed hER-beta but not hER-alpha may induce caspase-8-mediated apoptosis by increasing the hTNF-alpha gene expression in a ligand-dependent manner in poorly differentiated HA22T cells.
 ...
PMID:Opposing action of estrogen receptors alpha and beta on tumor necrosis factor-alpha gene expression and caspase-8-mediated apoptotic effects in HA22T cells. 1663 37

Nitric oxide (NO) and 17beta-estradiol (E2) are both important in gastrointestinal health and disease. NO contributes to gastrointestinal motility as well as to inflammation and carcinogenic processes. By contrast, E2 reduces the incidence of colon adenoma and carcinoma by about 30%. We report the genomic and non-genomic E2-estrogen receptor (ER) beta-induced effects in human colon adenocarcinoma. The effect of NO on ERbeta activities was also assessed. The E2-ERbeta-dependent gene transcription was inhibited by exogenous NO, whereas some non-genomic E2-dependent effects (e.g. p38/MAP kinase), important for the activation of the apoptotic cascade, were unaffected by NO. However, NO impaired the E2-induced pro-apoptotic cascade in human colon adenocarcinoma cells by inhibiting caspase-3. The effects of NO may reflect chemical modification(s) of Cys residues present in the DNA recognition domain of ERbeta as well as in the caspase-3 active site. On the whole, high NO concentrations suppressed the E2 protective effects in the gastrointestinal tract, suggesting that the caspase-dependent apoptotic cascade may become critical under conditions of high redox stress such as occur under specific activation of the immune system by chronic infections or pathogen challenge.
 ...
PMID:Nitric oxide impairs the 17beta-estradiol-induced apoptosis in human colon adenocarcinoma cells. 1672 82

Our recent study showed that estrogen receptor (ER) beta plays a major role in mediating the salutary effects of 17beta-estradiol (E2) on cardiac function following trauma-hemorrhage (T-H). E2 is known to regulate mitochondrial DNA (mtDNA)-encoded genes including the mitochondrial respiratory complex (MRC) proteins. Depressed MRC activity has been reported to promote the release of cytochrome c from mitochondria and induce apoptosis. We hypothesized that E2 and ERbeta-mediated cardioprotection following T-H is dependent on mtDNA transcription encoding for MRC activity. To test this, male rats underwent T-H (mean BP 40 mm Hg approximately 90 min, then resuscitation). During resuscitation, rats received either ERalpha agonist propylpyrazole triol (PPT; 5 microg/kg), ERbeta agonist diarylpropionitrile (DPN; 5 microg/kg), E2 (50 microg/kg), or vehicle (10% DMSO). Another group of rats received mitochondrial respiratory complex-IV (MRC-IV) inhibitor sodium cyanide (SCN; 6 mg/kg) with or without DPN. The results indicated that 24 h after T-H, cardiac functions were depressed in the vehicle-treated but were normal in the DPN-treated rats. Moreover, E2 or DPN treatment after T-H normalized cardiac mitochondrial ERbeta expression and increased mitochondrial ERbeta DNA-binding activity. This was accompanied by an increase in MRC-IV gene expressions and activity, while MRC-I gene expression remained unchanged. Inhibition of MRC-IV in DPN-treated T-H rats by SCN abolished the DPN-mediated cardioprotection, ATP production, mitochondrial cytochrome c release, caspase-3 cleavage, and apoptosis. Thus, E2 and ERbeta-mediated cardioprotection following T-H appears to be mediated via mitochondrial ERbeta-dependent MRC-IV activity and inhibition of mitochondrial apoptotic signaling pathways.
 ...
PMID:Upregulation of mitochondrial respiratory complex IV by estrogen receptor-beta is critical for inhibiting mitochondrial apoptotic signaling and restoring cardiac functions following trauma-hemorrhage. 1685 1

Women are at high risk of dying from unrecognized cardiovascular disease. Many differences in cardiovascular disease between men and women appear to be mediated by vascular smooth muscle cells (SMC). Because estrogen reduces the proliferation of SMC, we hypothesized that activation of estrogen receptor-alpha (ERalpha) by agonists or by growth factors altered SMC function. To determine the effect of growth factors, estrogen, and ERalpha expression on SMC differentiation, human aortic SMC were cultured in serum-free conditions for 10 days. SMC from men had lower spontaneous expression of ERalpha and higher levels of the differentiation markers calponin and smooth muscle alpha-actin than SMC from women. When SMC containing low expression of ERalpha were transduced with a lentivirus containing ERalpha, activation of the receptor by ligands or growth factors reduced differentiation markers. Conversely, inhibiting ERalpha expression by small interfering RNA (siRNA) in cells expressing high levels of ERalpha enhanced the expression of differentiation markers. ERalpha expression and activation reduced the phosphorylation of Smad2, a signaling molecule important in differentiation of SMC and initiated cell death through cleavage of caspase-3. We conclude that ERalpha activation switched SMC to a dedifferentiated phenotype and may contribute to plaque instability.
 ...
PMID:Activation of estrogen receptor-alpha reduces aortic smooth muscle differentiation. 1694 40

Since there is evidence for estrogen and estrogen-like compounds to have beneficial effect on the pathogenesis of hepatocellular carcinoma (HCC), this study was designed to investigative the apoptotic and anti-proliferative effects of these compounds on the human hepatoma Hep3B cell line. The Hep3B cells were treated with 17beta-estradiol (E2), diethylstilbestrol (DES), tamoxifen, and genistein. After treatments of these compounds at the concentration of 10(-6) or 10(-8) M, the Hep3B cells were demonstrated to have significant DNA fragmentation, nucleus condensation, cytochrome-c leaking from the mitochondria and caspase-3 activation by DAPI and Western blotting. The cells were also observed to have declined proliferative potential by MTT assay, arrested cell cycle by flow-cytometry measurements. However, the cytochrome-c leaking from the mitochondria induced by E2 and E2-like compounds was blocked totally by ICI 182,780 treatment. These finding suggest that estrogen and the estrogen-like compounds may induce anti-proliferative and apoptotic effects in Hep3B cells, and the E2 and the E2-like compounds mediated apoptotic effect was estrogen receptor dependent. Among the drugs tested, E2, E2 agonists (DES and genistein) and partial antagonist (tamoxifen), all showed the stronger anti-tumor potential.
 ...
PMID:Apoptotic and anti-proliferative effects of 17beta-estradiol and 17beta-estradiol-like compounds in the Hep3B cell line. 1692 24

Estrogens are developmental regulators of mitochondrial apoptotic pathway in the central nervous system, but little is known about their involvement in cytokine-induced apoptosis. In the present study, we evaluated effects of 17beta-estradiol on pro-inflammatory cytokine- and staurosporine-mediated activation of caspase-3 and LDH-release in primary neuronal/glial cell cultures of mouse hippocampal and neocortical cells at different stages of their development in vitro. Enzyme activities were determined with colorimetric methods 6 h, 14 h, 24 h, and 48 h after exposure to the apoptotic agents. Biochemical data were supported at the cellular level by Hoechst 33342 and MAP-2 stainings, which were carried out 48 h after the treatment. Cytokines (co-treatment with Il-1beta and TNFalpha; 1 ng/ml) increased caspase-3 activity in the hippocampal and neocortical cells up to over 200% of control values, and these effects were mostly observed on 2 and 7 days in vitro (DIV). Moderate, but significant cytokine-mediated increase in LDH-release was demonstrated in both tissues, especially on 7 and 12 DIV. Estradiol (100 nM) inhibited the activation of caspase-3 at early stage of development (2 DIV) in the hippocampal, but not in the neocortical cultures. The cytokine-induced activation of caspase-3 and LDH-release was inhibited by estradiol in estrogen receptor-independent way. These data point to a possible role of estrogens as non-estrogen receptor-related inhibitors of cytokine-activated apoptotic pathway in the developing central nervous system.
 ...
PMID:Impact of 17beta-estradiol on cytokine-mediated apoptotic effects in primary hippocampal and neocortical cell cultures. 1694 56

Two flavonoids, genistein and apigenin, have been implicated as chemopreventive agents against prostate and breast cancers. However, the mechanisms behind their respective cancer-protective effects may vary significantly. The goal of this study was to determine whether the antiproliferative action of these flavonoids on prostate (DU-145) and breast (MDA-MB-231) cancer cells expressing only estrogen receptor (ER) beta is mediated by this ER subtype. It was found that both genistein and apigenin, although not 17beta-estradiol, exhibited antiproliferative effects and proapoptotic activities through caspase-3 activation in these two cell lines. In yeast transcription assays, both flavonoids displayed high specificity toward ERbeta transactivation, particularly at lower concentrations. However, in mammalian assay, apigenin was found to be more ERbeta-selective than genistein, which has equal potency in inducing transactivation through ERalpha and ERbeta. Small interfering RNA-mediated downregulation of ERbeta abrogated the antiproliferative effect of apigenin in both cancer cells but did not reverse that of genistein. Our data unveil, for the first time, that the anticancer action of apigenin is mediated, in part, by ERbeta. The differential use of ERalpha and ERbeta signaling for transaction between genistein and apigenin demonstrates the complexity of phytoestrogen action in the context of their anticancer properties.
 ...
PMID:Apigenin suppresses cancer cell growth through ERbeta. 1713 21

Phytoestrogens prevent neuronal damage, however, mechanism of their neuroprotective action has not been fully elucidated. This study aimed to evaluate the effects of genistein on glutamate-induced apoptosis in mouse primary neuronal cell cultures. Glutamate (1 mM) enhanced caspase-3 activity and lactate dehydrogenase (LDH) release in the hippocampal, neocortical and cerebellar neurons in time-dependent manner, and these data were confirmed at the cellular level with Hoechst 33342 and calcein AM staining. Genistein (10-10,000 nM) significantly inhibited glutamate-induced apoptosis, and the effect of this isoflavone was most prominent in the hippocampal cells. Next, we studied an involvement of estrogen and aryl hydrocarbon receptors in anti-apoptotic effects of genistein. A high-affinity estrogen receptor antagonist, ICI 182, 780 (1 microM), reversed, whereas less specific antagonist/partial agonist, tamoxifen (1 microM), either intensified or partially inhibited genistein effects. Aryl hydrocarbon receptor antagonist, alpha-naphthoflavone (1 microM), exhibited a biphasic action: it enhanced genistein action toward a short-term exposure (3 h) to glutamate, but antagonized genistein action toward prolonged exposure (24 h) to that insult. SB 216763 (1 microM), which preferentially inhibits glycogen synthase kinase-3beta (GSK-3beta), potentiated genistein effects. These data point to strong effects of genistein at low micromolar concentrations in various brain tissues against glutamate-evoked apoptosis. Moreover, this study provided evidence for involvement of aryl hydrocarbon receptor and estrogen receptor/GSK-3beta intracellular signaling pathway in anti-apoptotic action of genistein.
 ...
PMID:Genistein inhibits glutamate-induced apoptotic processes in primary neuronal cell cultures: an involvement of aryl hydrocarbon receptor and estrogen receptor/glycogen synthase kinase-3beta intracellular signaling pathway. 1726 53


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>