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)

Oxidative stress has been suggested to play a central role in the pathogenesis of lung fibrosis and lung epithelial cell apoptosis is considered to be a key event during fibrogenesis. Studies from various laboratories have indicated that metabolic conditions may initiate oxidative stress, thereby contributing to epithelial cell death. This study was designed to test the hypothesis that glyoxal, an intermediate product in the glycation reaction leading to advanced glycation end products (AGEs), may induce lung epithelial cell apoptosis. We investigated the in vitro effects of glyoxal on fetal human lung epithelial L132 cells. Immunocytochemical analysis of paraffin-embedded cells and fluorescence-activated cell sorter analysis revealed a dose-dependent accumulation of the glycoxidation product (epsilon)N-carboxymethyllysine (CML) in all compartments of the cell. It has been shown that CML modification of proteins may serve as an indicator for oxidative stress. To examine the role of apoptosis in epithelial lung cells we investigated glyoxal-dependent changes in pro- and antiapoptotic mediators bax and activated caspase-3, and galectin-3 and bcl-2, respectively. Increasing concentrations of glyoxal (50 to 400 microM) induced an increase in the number of apoptotic cells. The apoptotic changes were confirmed by transmission electron microscopy. Immunocytochemical analysis of treated cells revealed the presence of other AGEs such as pentosidine as well as products of lipid peroxidation.
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PMID:Induction of apoptosis by glyoxal in human embryonic lung epithelial cell line L132. 1101 13

The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) induces apoptosis in a variety of human cancer cells including breast carcinoma and this property may be important for its chemopreventive and therapeutic effects. Resistance to 4HPR has been described, however, the molecular mechanisms underlying sensitivity or resistance to this retinoid are not clear. Recently, it has been shown that the carbohydrate-binding protein galectin-3, which has been implicated in tumor progression, contains the anti-death motif NWGR present in the anti-apoptotic protein Bcl-2. To determine whether galectin-3 expression can abrogate the effect of 4HPR, we tested the effects of 4HPR on apoptosis of cell clones derived from the galectin-3 deficient human BT549 breast carcinoma cells after transfection with either wild type galectin-3 (BT549Gal-3Wt), galectin-3 inactivated by a point mutation in the NWGR motif (BT549Gal-3Mu), or empty vector control (BT549Vec). Both BT549Vec and BT549Gal-3Mu cells showed a marked decrease in survival after treatment with 4HPR principally due to induction of apoptosis. 4HPR-induced apoptosis in these cells was associated with stimulation of reactive oxygen species generation, decreased levels of Bcl-2 protein, release of cytochrome c into the cytosol, increased caspase-3 activity, and poly(ADP-ribose) polymerase cleavage. In contrast, 4HPR failed to exert any of these effects in the BT549Gal-3Wt cells. The demonstration that galectin-3 suppresses 4HPR-induced apoptosis in human breast carcinoma cells suggests that the increased expression of galectin-3 during cancer progression may be associated with 4HPR resistance.
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PMID:Inhibition of N-(4-hydroxyphenyl)retinamide-induced apoptosis in breast cancer cells by galectin-3. 1532 75

Human multiple myeloma is a presently incurable hematologic malignancy, and novel biologically based therapies are urgently needed. GCS-100 is a polysaccharide derived from citrus pectin in clinical development for the treatment of cancer. Here we show that GCS-100 induces apoptosis in various multiple myeloma cell lines, including those resistant to dexamethasone, melphalan, or doxorubicin. Examination of purified patient multiple myeloma cells showed similar results. Specifically, GCS-100 decreases viability of bortezomib/PS-341-resistant multiple myeloma patient cells. Importantly, GCS-100 inhibits multiple myeloma cell growth induced by adhesion to bone marrow stromal cells; overcome the growth advantage conferred by antiapoptotic protein Bcl-2, heat shock protein-27, and nuclear factor-kappaB; and blocks vascular endothelial growth factor-induced migration of multiple myeloma cells. GCS-100-induced apoptosis is associated with activation of caspase-8 and caspase-3 followed by proteolytic cleavage of poly(ADP-ribose) polymerase enzyme. Combined with dexamethasone, GCS-100 induces additive anti-multiple myeloma cytotoxicity associated with mitochondrial apoptotic signaling via release of cytochrome c and Smac followed by activation of caspase-3. Moreover, GCS-100 + dexamethasone-induced apoptosis in multiple myeloma cells is accompanied by a marked inhibition of an antiapoptotic protein Galectin-3, without significant alteration in Bcl-2 expression. Collectively, these findings provide the framework for clinical evaluation of GCS-100, either alone or in combination with dexamethasone, to inhibit tumor growth, overcome drug resistance, and improve outcome for patients with this universally fatal hematologic malignancy.
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PMID:A novel carbohydrate-based therapeutic GCS-100 overcomes bortezomib resistance and enhances dexamethasone-induced apoptosis in multiple myeloma cells. 1616 12

We investigated the potential of the cytotoxic enterotoxin (Act) of Aeromonas hydrophila to bind to 1869 human and 4319 yeast proteins, using protein microarray technology. Act was capable of binding nine different human proteins, including the SNARE complex scaffolding protein synaptosomal-associated protein 23 (SNAP23), galectin-3, and guanylate kinase 1 (GUK-1). Act was also able to bind to four of the yeast proteins examined, which included the vesicle tethering protein Vsp52. We verified interaction of Act with murine and human SNAP23, galectin-3, and GUK-1 by sandwich Western blot analysis. In order to determine the physiological relevance of Act binding to these three proteins, we performed small interfering RNA (siRNA) gene knockdown experiments in RAW 264.7 cells, a murine macrophage cell line in which Act-induced signaling and cell death is well characterized. Based on real-time reverse transcriptase-polymerase chain reaction, siRNA transfection of RAW 264.7 cells with specific oligonucleotides reduced the expression of genes encoding SNAP23, galectin-3, and GUK-1 by 62, 63, and 99%, respectively. Knockdown of galectin-3 and SNAP23, but not GUK-1, significantly reduced Act-induced apoptosis of host cells, as determined by TUNEL (TdT-mediated dUTP nick end labeling) assay, lactate dehydrogenase release, Giemsa staining, and reduction in activation of caspase 3, compared to toxin-treated macrophages that were transfected with a random sequence control siRNA. We also performed these assays using a human intestinal epithelial cell line (HT-29) and observed a similar trend of galectin-3 and SNAP23 association with Act-induced apoptosis. This is the first report of putative protein binding partners for this toxin and potential mediators/regulators of Act-induced apoptosis.
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PMID:Potential involvement of galectin-3 and SNAP23 in Aeromonas hydrophila cytotoxic enterotoxin-induced host cell apoptosis. 1642 11

Prostate cancer is one of the malignant tumors which exhibit resistance to anticancer drugs, at least in part due to enhanced antiapoptotic mechanisms. Therefore, the understanding of such mechanisms should improve the design of chemotherapy against prostate cancer. Galectin-3 (Gal-3), a multifunctional oncogenic protein involved in the regulation of tumor proliferation, angiogenesis, and apoptosis has shown antiapoptotic effects in certain cell types. Here, we show that the expression of exogenous Gal-3 in human prostate cancer LNCaP cells, which do not express Gal-3 constitutively, inhibits anticancer drug-induced apoptosis by stabilizing the mitochondria. Thus, Gal-3-negative cells showed 66.31% apoptosis after treatment with 50 micromol/L cis-diammine-dichloroplatinum for 48 hours, whereas two clones of Gal-3-expressing cells show only 2.92% and 1.42% apoptotic cells. Similarly, Gal-3-negative cells showed 43.8% apoptosis after treatment with 300 micromol/L etoposide for 48 hours, whereas only 15.38% and 14.51% of Gal-3-expressing LNCaP cells were apoptotic. The expression of Gal-3 stimulated the phosphorylation of Ser(112) of Bcl-2-associated death (Bad) protein and down-regulated Bad expression after treatment with cis-diammine-dichloroplatinum. Gal-3 also inhibited mitochondrial depolarization and damage after translocation from the nuclei to the cytoplasm, resulting in inhibition of cytochrome c release and caspase-3 activation. These findings indicate that Gal-3 inhibits anticancer drug-induced apoptosis through regulation of Bad protein and suppression of the mitochondrial apoptosis pathway. Therefore, targeting Gal-3 could improve the efficacy of anticancer drug chemotherapy in prostate cancer.
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PMID:Galectin-3 regulates mitochondrial stability and antiapoptotic function in response to anticancer drug in prostate cancer. 1654 Jun 61

We investigated the effect of UVA-activated 8-methoxypsoralen (PUVA) on the cell line Karpas 299 derived from anaplastic large-cell lymphoma (ALCL) expressing chimeric fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM/ALK). NPM/ALK activates phosphatidylinositol 3 kinase (PI3K)/Akt pathway responsible for the cell protection from apoptosis. We found that PUVA treatment first induced G2/M cell cycle arrest resulting in a decrease in the cell proliferation rate. The mitochondrial apoptosis was triggered immediately following PUVA treatment, as we judged from the unmasking of mitochondrial membrane antigen 7A6. However, the mitochondrial membrane depolarization was not observed and caspase-3 was only slightly activated. The late apoptotic events were lacking: neither translocation of phosphatidylserine to the outer side of plasma membrane nor DNA fragmentation occurred. We revealed that PUVA enhanced the expression of peroxiredoxin, stress protein endoplasmin and galectin-3. Galectin-3 has been shown to protect mitochondrial membrane integrity and prevent cytochrome c release thereby blocking the effector stage of apoptosis. We suggest that the elevated level of this protein following PUVA treatment acts in synergy with the constitutively expressed chimeric kinase NPM/ALK to block the apoptosis.
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PMID:UVA-activated 8-methoxypsoralen (PUVA) causes G2/M cell cycle arrest in Karpas 299 T-lymphoma cells. 1673 25

Considering that several pathways leading to cell death are activated in cerebral ischemia, we tested in mouse models of transient and permanent ischemia a drug cocktail aiming at distinct pharmacological targets during the evolution of ischemic injury. It consists of minocycline--an antibiotic with anti-inflammatory properties, riluzole--a glutamate antagonist, and nimodipine--a blocker of voltage-gated calcium channels. Administered 2 h after transient or permanent MCAO, it significantly decreased the size of infarction, by approximately 65% after transient and approximately 35% after permanent ischemia and markedly improve clinical recovery of mice. In both experimental models a three-drug cocktail achieved significantly more efficient neuroprotection than any of the components tested alone. However, some interesting observation emerged from the single-drug studies. Treatment with minocycline alone was efficient in both experimental models while treatment with glutamate antagonist riluzole conferred neuroprotection only after transient MCAO. Immunohistochemical analysis following three-drug treatment revealed reduced microglia/macrophages and caspase-3 activation as well as preserved GFAP immunoreactivity following transient ischemia. No detectable differences in the levels of Mac-2, GFAP and caspase-3 immunoreactivities were observed 72 h after permanent MCAO. These marked differences in the brain tissue responses to ischemic injury and to treatments suggest that different pathological mechanisms may be operating in transient and permanent ischemia. However, the three-drug cocktail exerted significant neuroprotection in both experimental models thus demonstrating that simultaneous targeting of several pathophysiological pathways involved in the evolution of ischemic injury may represent a rational therapeutic strategy for stroke.
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PMID:Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia. 1723 87

Galectin-3 (GAL3), a beta-galactoside-binding lectin, confers chemoresistance to a wide variety of cancer cell types. It may exhibit anti- or pro-apoptotic activity depending on the nature of the stimulus. We report here that introducing phosphorylated galectin-3 (P-GAL3) into GAL3-null, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant human breast carcinoma cells promotes TRAIL-induced apoptotic cell death by stimulating the phosphorylation/inactivation of the pro-apoptotic molecule Bad resulting in the inhibition of mitochondrial depolarization and the release of cytochrome c. Exposure of the transfectant cells to TRAIL leads to the recruitment of the initiator capase-8 followed by activation of the effector caspase-9, independent of cytochrome c, and subsequently the processing of the executioner caspase-3. P-GAL3 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) were coordinately expressed, with concomitant dephosphorylation of Akt in TRAIL-sensitive cells. In contrast, overexpression of phospho-mutant GAL3 (incapable of phosphorylation) failed to elicit similar responses. Depletion of PTEN using small interference RNAs reinstated Akt phosphorylation and conferred TRAIL resistance. In addition phosphatidylinositol 3-kinase inhibitors rendered the phospho-mutant GAL3-resistant cells sensitive to TRAIL. These findings suggest a pivotal role for P-GAL3 in promoting TRAIL sensitivity through activation of a nonclassic apoptotic pathway and identify P-GAL3 as a novel regulator of PTEN.
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PMID:Phosphorylated galectin-3 mediates tumor necrosis factor-related apoptosis-inducing ligand signaling by regulating phosphatase and tensin homologue deleted on chromosome 10 in human breast carcinoma cells. 1742 Feb 49

Pectic polysaccharides from dietary sources such as Decalepis hamiltonii--swallow root (SRPP), Hemidesmus indicus (HPP), Nigella sativa--black cumin (BCPP), Andrographis serpyllifolia-(APP), Zingiber officinale--ginger (GRPP) and, citrus pectin (CPP) were examined for galectin inhibitory activity. Inhibition of (a) galectin-3 of MDA-MB-231 cells induced hemagglutination of red blood cells; (b) galectin-3 mediated interaction between normal/metastatic human buccal cells (NBC)/(MBC) and; (c) invasion of MDA-MB-231 and MBC in the invasive chamber was assessed. Results indicated that SRPP inhibited hemagglutination at Minimum Inhibitory Concentration (MIC) of 1.86 microg ml(-1) equivalent of carbohydrate as apposed to those of BCPP (130 microg ml(-1)), APP (40 microg ml(-1)), HPP (40 microg ml(-1)) and CPP (25 microg ml(-1)). GRPP even at concentration >1-6 mg ml(-1) did not inhibit agglutination. Also SRPP showed approximately 15 and 2 fold potent anti hemagglutination activity relative to that of galectin-3 specific sugars-galactose (MIC-27.1 microg ml(-1)) and lactose (MIC-4.16 microg ml(-1)) respectively. Further, SRPP at 10 microg ml(-1) inhibited agglutination of NBC by galectin-3 of MDA-MB-231 cells. Modified swallow root pectic polysaccharide (MSRPP) of 50 kDa retained anti hemagglutination activity (MIC of 1.03 microg ml(-1)) and inhibited MDA-MB-231 and MBC invasion by 73 and 50% with an IC(50) of 136 and 200 microg ml(-1) respectively. Both SRPP and MSRPP induced apoptosis up to 80% at 100 microg ml(-1) concentration by activating approximately 2 and 8 folds of Caspase-3 activity. Sugar composition analysis and its correlation with the galectin inhibitory property indicated that pectic polysaccharides with higher arabinose and galactose content-arabinogalactan inhibited hemagglutination significantly.
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PMID:Inhibition of galectin-3 mediated cellular interactions by pectic polysaccharides from dietary sources. 1752 29

Galectin-1 and galectin-3 are the most ubiquitously expressed members of the galectin family and more importantly, these two molecules are shown to have opposite effects on pro-inflammatory responses and/or apoptosis depending on the cell type. Herein, we demonstrate for the first time that galectin-3 induces mast cell apoptosis. Mast cells expressed substantial levels of galectin-3 and galectin-1 and to a lesser extent the receptor for advanced glycation end products (RAGE) on their surfaces. Treatment of cells with galectin-3 at concentrations of > or =100 nM for 18-44 h resulted in cell death by apoptosis. Galectin-3-induced apoptosis was completely prevented by lactose, neutralizing antibody to RAGE, and the caspase-3 inhibitor z-DEVD-fmk. Galectin-3-induced apoptosis was also completely abolished by dithiothreitol and superoxide dismutase, but not inhibited by catalase. Moreover, galectin-3 but not galectin-1 induced the release of superoxide, which was blocked by lactose, anti-RAGE, and dithiothreitol. Finally, galectin-3-induced apoptosis was blocked by bongkrekic acid, an antagonist of the mitochondrial permeability transition pore (PTP), while atractyloside, an agonist of the PTP, greatly facilitated galectin-1-induced apoptosis. These data suggest that galectin-3 induces oxidative stress, PTP opening, and the caspase-dependent death pathway by binding to putative surface receptors including RAGE via the carbohydrate recognition domain.
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PMID:Galectin-3 but not galectin-1 induces mast cell death by oxidative stress and mitochondrial permeability transition. 1830 39


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