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

Phosphatidic acid (PA), the product of a PLD-mediated reaction, is a lipid second messenger that participates in various intracellular signaling events and is known to regulate a growing list of signaling proteins. We found that Bcl-2 was upregulated by PA treatment in HeLa cells. However, how PA upregulates Bcl-2 expression has not yet been studied. In this study, we tried to discover the mechanisms of Bcl-2 up-regulation by PA treatment in HeLa cells. Treatment with PA resulted in significantly increased expression of Bcl-2 in HeLa cells. Moreover, PA-induced Bcl-2 expression was blocked by mepacrine, an inhibitor of PLA2, but not by propranolol, an inhibitor of PA phospholyhydrolase (PAP). Treatment of 1,2-dipalmitoryl-sn-glycero-3- phosphate (DPPA) also increased Bcl-2 expression. These results indicate that Bcl-2 expression is mediated by lysophosphatidic acid (LPA), not by arachidonic acid (AA). Thereafter, we used MEK1/2 inhibitor, PD98059 to investigate the relationship between ERK1/2 MAPK and PA-induced Bcl-2 expression. PA-induced Bcl-2 expression was decreased when ERK1/2 was inhibited by PD98059. The transcription factor such as STAT3 which is controlled by ERK1/2 MAPK was increased along with Bcl-2 expression when the cells were treated with PA. Furthermore, STAT3 siRNA treatments inhibited PA-induced Bcl-2 expression, suggesting that STAT3 (Ser727) is involved in PA-induced Bcl-2 expression. Taken together, these findings indicate that PA acts as an important mediator for increasing Bcl-2 expression through STAT3 (Ser727) activation via the ERK1/2 MAPK pathway.
 ...
PMID:STAT3 is involved in phosphatidic acid-induced Bcl-2 expression in HeLa cells. 1928 90

Expression of STAT3/pSTAT3 in colorectal cancer (CRC) patients of Indian origin was studied to assess its significance in early detection and apoptosis regulation. Colorectal tissues with malignant lesions were STAT3/pSTAT3 positive in 66% of the cases and among these positive cases, well differentiated, moderately differentiated and poorly differentiated cancers were 86%, 60% and 0% respectively. All CRC specimens studied were immunoreactive with anti-carcinoembryonic antigen antibody. Cells purified from CRC tissues exhibited greater STAT3/pSTAT3 reactivity than peripheral blood mononuclear cells (PBMC) from healthy individuals, which served as control. apoptotic index (AI) was comparatively low in tissue specimens with STAT3/pSTAT3 expression. CRC cells with a comparatively less number of apoptotic cells, expressed a minimum number of Caspase-3 positive cells (4.73%), in comparison to healthy-PBMC (12.63%). CRC cells with high STAT3/pSTAT3 staining had cells with greater percentage of Bcl2 reactivity (23.05%), but less positivity with Caspase3 antibody (2.05%). Overall data suggests that CRC population was STAT3/pSTAT3 immunoreactive in a stage specific manner and STAT3 protects cancerous colorectal epithelial cells from apoptosis. Bcl-2, Cyclin D1 and Caspase-3 control the activity of apoptosis regulator, STAT3.
 ...
PMID:Association of early phase of colorectal carcinogenesis with STAT3 activation and its relevance in apoptosis regulation. 1934 26

ZD6474 is an orally available, small-molecule tyrosine kinase inhibitor. This study explores the effect of ZD6474 on imatinib-resistant K562 cell lines, which show markedly increased SRC family kinases (SFKs) activity. ZD6474 induces growth arrest and apoptosis of imatinib-resistant and parental K562 cells, as well as inhibition of Src activity and its downstream effectors, the anti-apoptotic Bcl-2 family. ZD6474 treatment also inhibits the activity of STAT3 and reactivation of its activity results in suppression of the anti-tumor effects of SFKs inhibitors. A single oral administration of ZD6474 produced dose-dependent inhibition of imatinib-resistant K562 cells xenograft tumors. These results suggest that clinical assessment of ZD6474 against imatinib-resistant CML is warranted.
 ...
PMID:ZD6474 inhibits Src kinase leading to apoptosis of imatinib-resistant K562 cells. 1939 92

Aspirin has been reported to induce apoptosis in various cancer cell lines. However, the apoptotic effects of aspirin on human brain tumor cells are not well understood. Here, we have assessed the effect of aspirin on human gliobalstoma cell line A172 and found that aspirin induced the apoptosis of A172 cells, as determined by TUNEL assay, FACS analysis, and Hoechst staining. The underlying mechanism of this effect consists of reduction in the level of phosphorylated STAT3 (Tyr705), a transcription factor required for survival of A172 cells. Moreover, the expression of STAT3 target genes such as Cyclin D1, XIAP, and Bcl-2 that are essential for cell growth and survival was apparently attenuated after aspirin treatment. We also showed that the expression and secretion of interleukin-6 (IL-6), leading to STAT3 phosphorylation, was inhibited by aspirin. When administered exogenous IL-6 to aspirin-treated A172 cells, the phosphorylation of STAT3 and cellular apoptosis were restrained compared to aspirin only-treated cells. Taken together, our results indicate that aspirin causes apoptosis via down-regulation of IL-6-dependent STAT3 signaling, suggesting that aspirin could be therapeutically useful for a potential anti-glioblastoma therapeutic approach.
 ...
PMID:Aspirin induces apoptosis through the blockade of IL-6-STAT3 signaling pathway in human glioblastoma A172 cells. 1959 69

Interleukin 6 (IL-6) is a pleiotropic cytokine that is highly expressed in response to ischemia and reperfusion. It has dichotomous roles in the heart, functioning both as an inflammatory mediator as well as a protective agent. The aim of this study was to evaluate the effect of IL-6 deficiency on the expression of apoptotic regulatory proteins under both baseline conditions and following induction of ischemia and reperfusion in the mouse heart. C57BL/6J IL-6-/-(TMKopf) (IL6KO) and C57BL/6J mice (WT) were subjected to 30 minutes of local reversible myocardial ischemia in vivo or a sham operation. The expression of Bcl-2, Bax and STAT3 in the heart was assessed by western blotting. Under both baseline conditions and following the sham operation, IL-6 deficiency was associated with reduced expression of Bcl-2 and Bax. The TUNEL-FITC, Evans blue and tetrazolium chloride staining of the hearts following ischemia and reperfusion revealed similar injury in operated IL6KO and WT animals. There was increased STAT3 phosphorylation in operated mice regardless of the genotype. Bcl-2 and Bax expression was also comparable between the mouse strains following ischemia and reperfusion. In summary, these results indicated that IL-6 deficiency affected the basal expression of apoptotic regulators, but this did not profoundly alter the extent of reperfusion injury or apoptosis in the mouse heart following ischemia and reperfusion.
 ...
PMID:Effect of interleukin 6 deficiency on the expression of Bcl-2 and Bax in the murine heart. 1960 50

The combination of ATO and bortezomib (ATO+bortezomib) has been recently shown to enhance antimyeloma activity; nevertheless, the mechanisms remained unclear in these studies. However, both bortezomib and ATO have been shown to activate the p38 MAPK pathway, which may counteract the enhancement induced by this combination. We studied the cytotoxicity of bortezomib, ATO, and ATO+bortezomib with or without inhibiting p38 MAPK, along with associated molecular changes in myeloma cells. The treatment of myeloma cells with ATO+bortezomib induced higher cytotoxicity than either agent alone. This increased cytotoxicity was further synergistically enhanced by inhibiting p38 MAPK. This effect was preserved in the presence of marrow stromal cells designed to simulate the tumor micro-environment and in the CD138+ neoplastic plasma cells directly isolated from myeloma patients. The enhanced cytotoxicity of ATO+bortezomib was associated with augmented STAT3 inhibition and JNK activation, up-regulation of Bim, p21, p27, p53 as well as down-regulation of Bcl-2. Furthermore, the synergistically potentiated apoptosis by p38 MAPK inhibition was associated with the attenuation of ATO+bortezomib-mediated activation of Hsp27 as well as the enhancement of ATO+bortezomib-mediated JNK activation, p53 up-regulation, and Bcl-2 down-regulation. The results suggest the opportunity for using p38 MAPK inhibition to enhance the efficacy of ATO+bortezomib in myeloma.
 ...
PMID:Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition. 1960 75

Cardiotoxin III (1), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has potential therapeutic activity in cancer. Treatment with 1 reduced phosphorylation of EGFR and Akt, as well as ERK in Ca9-22 cells. Moreover, 1-treatment inhibited constitutive activation of STAT3 and STAT5 in a time-dependent manner. Up-regulation of Bax and down-regulation of anti-apoptotic proteins including Bcl-2, Bcl-X(L), and myeloid cell leukemia-1(Mcl-1) were also found in cells treated with 1. In addition, 1-treatment disrupted mitochondrial membrane potential (DeltaPsim) and resulted in release of mitochondrial cytochrome c and activation of both caspases-9 and -3. AG1478, a specific pharmacological inhibitor of EGFR activation, mimics the cytotoxic effects of 1. Taken together, these results showed that 1 causes significant induction of apoptosis in Ca9-22 cells via abolition of the EGFR-mediated survival pathway of these cells. Thus, cardiotoxin III appears to be a potential therapeutic agent for killing oral squamous carcinoma Ca9-22 cells.
 ...
PMID:Inactivation of epidermal growth factor receptor and downstream pathways in oral squamous cell carcinoma Ca9-22 cells by cardiotoxin III from Naja naja atra. 1975 29

Resveratrol is a natural occurring phytoalexin present in grapes and berries, that has been shown to have chemopreventive/therapeutic activity. But the precise mechanism of resveratrol involved in leukemia is not well understood. In this study, we examine its anti-leukemia effect both in vitro and in vivo. Our data indicate that resveratrol contributes to inhibiting growth, inducing apoptosis and cell cycle arrest in the three leukemia cell lines (Jurkat, SUP-B15, and Kasumi-1), and reducing the phosphorylation of STAT3, meanwhile modulating the expression of Bcl-2 and Bax. In vivo, resveratrol could prolong the life span of Kasumi-1-bearing mice, and attenuate the activity of STAT3. Taken altogether, this investigation focuses on signaling pathways involved in STAT3 by resveratrol and to delineate its molecular mechanisms underlying anti-leukemia effect.
 ...
PMID:Evaluation of anti-leukemia effect of resveratrol by modulating STAT3 signaling. 1979 11

This study was undertaken to determine the in vitro effect of lentivirus-mediated siPin1 on cell cycle and apoptosis of vascular smooth muscle cells (VSMCs). Further we sought to provide insight into the mechanisms behind these processes. Human umbilical artery smooth muscle cells (HUASMCs) were transfected with lentiviral siPin1. Real-time RT-PCR and Western blotting were used to examine Pin1 mRNA and protein expression. MTT and [(3)H]thymidine incorporation assays were employed to observe cell proliferation status. The apoptotic rate and cell cycle were analyzed by Hoechst33258 staining and flow cytometry. Finally we measured the expression of cyclin D1, beta-catenin, CDK4, cytochrome c, procaspase-3, cleaved caspase-3, procaspase-9, cleaved caspase-9, Bcl-2, Bax, STAT3, phosphorylated STAT3 and VEGF in lentiviral siPin1 infected VSMCs. Lentivirus-mediated siPin1 effectively diminished endogenous Pin1 expression in VSMCs resulting in cell cycle arrest and enhancement of apoptosis. This was accompanied by downregulation of cyclin D1, beta-catenin, CDK4, increase of Bax/Bcl-2 ratio, release of cytochrome c, and activation of caspase-3 and -9. We concluded that this effect was mediated, at least in part, via the beta-catenin/cyclin D1/CDK4 cascade, and that the mitochondrial pathway was responsible for VSMC apoptosis in the absence of Pin1. Our observations raised the possibility that Pin1 might be a potential therapeutic target to prevent stenosis.
 ...
PMID:Inhibition of peptidyl-prolyl cis/trans isomerase Pin1 induces cell cycle arrest and apoptosis in vascular smooth muscle cells. 1990 10

Nasal natural killer (NK)-cell lymphoma was resistant to various antitumor agents. Although high expression of p-glycoprotein has been reported, other molecular mechanism of the chemo-resistance is largely unknown. Activation of STAT3 and expression of major apoptosis-related proteins Bcl-2, Bcl-x, and Mcl-1 were analyzed by immunohistochemistry. Effects of STAT3 inhibitor AG490 on NK-YS cell line were analyzed by Western blotting and flow cytometric apoptosis assay. STAT3 was activated in six of the nine nasal NK-cell lymphomas (67%). In contrast, STAT3 activation was detected in 35% of diffuse large B-cell lymphoma (DLBCL) and in 10% of follicular lymphoma (FL). Frequent activation of STAT3 was significantly correlated with Mcl-1 expression in nasal NK-cell lymphoma, i.e., Mcl-1 was positive in five of six STAT3-active cases and negative in all three STAT3-inactive ones. In DLBCL, not only six out of seven STAT3-active cases (86%) but also eight out of thirteen STAT3-inactive cases (62%) were positive for Mcl-1 expression. Latent membrane protein-1 was positive in four nasal NK-cell lymphomas, among which three cases showed intermediate STAT3 activation. Inhibition of STAT3 activation by JAK inhibitor AG490 decreased Mcl-1 expression and induced apoptosis in STAT3-active NK-YS cells. Serum starvation rather increased the Mcl-1 level in NK-YS cells, and this effect was also canceled by AG490. These results suggest that activation of STAT3-Mcl-1 axis may play a role in the chemotherapy resistance of nasal NK-cell lymphoma. The pathway may be one of the future therapeutic targets of this intractable disease.
 ...
PMID:Frequent STAT3 activation is associated with Mcl-1 expression in nasal NK-cell lymphoma. 1996 19


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