UNIPROT:P10415 - FACTA Search

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Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the biological effects of nitric oxide (NO) and its mediator, heme oxygenase-1 (HO-1), in cancer. Urogenital cancer cell lines, SKRC, T24 and DU145, were treated with various concentrations of sodium nitroprusside (SNP), a NO donor. The medium nitrite concentration was exponentially increased according to the concentration of SNP. Cell growth inhibition by NO was observed only at high nitrite concentrations (>20 microM) in DU145 and T24 cells. Nitrite did not inhibit the growth of SKRC cells at any of the concentrations used. Doxorubicin (DXR) inhibited cell growth in the three cell lines, whereas growth inhibition recovered in the presence of <10 microM nitrite. The recovery of DXR-induced growth inhibition was closely associated with an increase in Bcl-2 in the presence of <10 microM nitrite. Vascular endothelial growth factor (VEGF) secretion was also increased in the presence of <10 and <20 microM nitrite, respectively, in DU145 and SKRC or T24 cells. The expression of HO-1 was associated with sensitivity to NO-induced growth inhibition at constitutive levels, and was induced by SNP treatment. HO-1 inhibition by HO-1 antisense S-oligodeoxynucleotide treatment increased NO-induced growth inhibition, and decreased Bcl-2 expression or VEGF secretion in the three cell lines. These findings suggest that the NO/HO-1 system has protumoral effects.
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PMID:Heme oxygenase-1 accelerates protumoral effects of nitric oxide in cancer cells. 1583 87

Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis of hepatocellular carcinoma. Inhibition of VEGF receptors could theoretically reduce angiogenesis and tumor growth in hepatocellular carcinoma, but this remains to be proven with an experimental study. This study examined the angiogenesis-dependent and angiogenesis-independent activities of PTK787/ZK222584 (PTK787), a tyrosine kinase inhibitor of VEGF receptors, in nude mice bearing human hepatocellular carcinoma xenografts. The in vitro effects of PTK787 on proliferation, apoptosis, and cell cycle distribution in human hepatocellular carcinoma cell lines were also studied. Oral administration of PTK787 resulted in a significant reduction in tumor volume and microvessel formation of hepatocellular carcinoma xenografts in nude mice. PTK787 inhibited tumor cell proliferation in a dose-dependent manner and also induced tumor cells to undergo apoptosis both in vivo and in vitro. The proapoptotic response was associated with down-regulation of Bcl-2 and Bcl-x(L) expression and induction of cleavage of caspase-3. In addition, PTK787 induced growth arrest in hepatocellular carcinoma cells, which was associated with G1 arrest and partial G2-M block. This effect correlated with an increase in p21(WAF1/ CIP1) (p21) and p27KIP1 (p27) protein expression. In conclusion, this study showed that PTK787 is a potent inhibitor of tumor growth in hepatocellular carcinoma by both antiangiogenic effect and direct effects on tumor cell proliferation and apoptosis. Our data suggest that blockage of VEGF receptors may provide an effective therapeutic approach for human hepatocellular carcinoma.
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PMID:Both antiangiogenesis- and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584. 1586 64

Vascular endothelial growth factor (VEGF) induces expression of Bcl-2 in tumor-associated microvascular endothelial cells. We have previously reported that up-regulated Bcl-2 expression in microvascular endothelial cells is sufficient to enhance intratumoral angiogenesis and to accelerate tumor growth. We initially attributed these results to Bcl-2-mediated endothelial cell survival. However, in recent experiments, we observed that conditioned medium from Bcl-2-transduced human dermal microvascular endothelial cells (HDMEC-Bcl-2) is sufficient to induce potent neovascularization in the rat corneal assay, whereas conditioned medium from empty vector controls (HDMEC-LXSN) does not induce angiogenesis. These results cannot be attributed to the role of Bcl-2 in cell survival. To understand this unexpected observation, we did gene expression arrays that revealed that the expression of the proangiogenic chemokines interleukin-8 (CXCL8) and growth-related oncogene-alpha (CXCL1) is significantly higher in HDMEC exposed to VEGF and in HDMEC-Bcl-2 than in controls. Inhibition of Bcl-2 expression with small interfering RNA-Bcl-2, or the inhibition of Bcl-2 function with small molecule inhibitor BL-193, down-regulated CXCL8 and CXCL1 expression and caused marked decrease in the angiogenic potential of endothelial cells without affecting cell viability. Nuclear factor-kappaB (NF-kappaB) is highly activated in HDMEC exposed to VEGF and HDMEC-Bcl-2 cells, and genetic and chemical approaches to block the activity of NF-kappaB down-regulated CXCL8 and CXCL1 expression levels. These results reveal a novel function for Bcl-2 as a proangiogenic signaling molecule and suggest a role for this pathway in tumor angiogenesis.
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PMID:Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines. 1595 49

Vascular endothelial growth factor-D (VEGF-D) stimulates growth of vascular and lymphatic endothelial cells by signaling through the tyrosine kinase receptors KDR (VEGFR-2) and Flt-4 (VEGFR-3). In the present study, we examined the effects of VEGF-D on apoptosis in human MCF-7 and MDA-MB-231 breast carcinoma cells. Because VEGF-D was not expressed constitutively in vitro, stable VEGF-D transfectants were produced. The VEGF-D-expressing MCF-7 and MDA-MB-231 lines displayed resistance to apoptosis induced by hypoxia, staurosporin and cycloheximide. Increased Bcl-2 expression, decreased homogenous caspase activities and inhibition of poly(ADP-ribose) polymerase cleavage were associated with inhibition of apoptosis in VEGF-D-expressing clones. Also, caspase-3 activation was suppressed in the VEGF-D expressing MDA-MB-231 clone. The antiapoptotic effect of VEGF-D in vitro was recapitulated in vivo using VEGF-D-expressing MDA-MB-231 xenografts. The lack of VEGFR-2 protein expression by Western blot and ineffectiveness of a neutralizing VEGFR-2 antibody in eliminating the antiapoptotic effects of VEGF-D suggest a different and yet unknown signaling mechanism. Our findings indicate that VEGF-D has a novel function as a survival factor of breast carcinoma cells in addition to its established functions as an angiogenic and lymphangiogenic factor.
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PMID:Vascular endothelial growth factor-D is a survival factor for human breast carcinoma cells. 1615 91

Angiogenesis is the development of blood capillaries from pre-existing vessels. Vascular endothelial growth factor (VEGF) is a key regulator of vessel growth and regression, and acts as an endothelial survival factor by protecting endothelial cells from apoptosis. Many genes involved in cell proliferation and apoptosis are regulated by the nuclear factor kappa B (NFkappaB) transcription factor family. This study aimed to address the hypothesis that VEGF-mediated survival effects on endothelium involve NFkappaB. Using an NFkappaB-luciferase reporter adenovirus, we observed activation of NFkappaB following VEGF treatment of human umbilical vein endothelial cells. This was confirmed using electrophoretic mobility shift assay and found to involve nuclear translocation of NFkappaB sub-unit p65. However, NFkappaB activation occurred without degradation of inhibitory IkappaB proteins (IkappaBalpha, IkappaBbeta, and IkappaBepsilon). Instead, tyrosine phosphorylation of IkappaBalpha was observed following VEGF treatment, suggesting NFkappaB activation was mediated by degradation-independent dissociation of IkappaBalpha from NFkappaB. Adenovirus-mediated over-expression of either native IkappaBalpha, or of IkappaBalpha in which tyrosine residue 42 was mutated to phenylalanine, inhibited induction of NFkappaB-dependent luciferase activity in response to VEGF. Furthermore, VEGF-induced upregulation of mRNA for the anti-apoptotic protein Bcl-2 and cell survival following serum withdrawal was reduced following IkappaBalpha over-expression. This study highlights that different molecular mechanisms of NFkappaB activation may be involved downstream of stimuli which activate the endothelial lining of blood vessels.
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PMID:Vascular endothelial growth factor signalling in endothelial cell survival: a role for NFkappaB. 1641 78

Vascular endothelial growth factor (VEGF) is produced by most tumour types and stimulates the growth of new blood vessels in the tumour. The expansion of a solid tumour ultimately leads to the development of hypoxic regions, which increases VEGF production and further angiogenesis. In this study, we examined the role of VEGF in the survival of breast tumour cells under hypoxia. Murine 4T1 and human MDA-MB-231 tumour cells were cultured under normoxic and hypoxic growth conditions in the presence or absence of VEGF neutralising antibodies. Apoptosis was assessed in addition to changes in expression of the anti- and pro-apoptotic proteins, Bcl-2 and Bad, respectively. The effect of hypoxia on the novel VEGF receptor, NP1 (neuropilin-1) and the role of the PI3K (phosphatidylinositol-3-kinase) signalling pathway in response to VEGF were examined. VEGF blockade resulted in direct tumour cell apoptosis of both tumour cell lines under normoxia and hypoxia. While blocking VEGF resulted in a downregulation of hypoxia-induced Bcl-2 expression, there was a significant increase in the pro-apoptotic protein Bad relative to cells cultured under hypoxia alone. Both hypoxia and VEGF phosphorylated Akt. Neutralising antibodies to VEGF abrogated this effect, implicating the PI3K pathway in VEGF-mediated cell survival of mammary adenocarcinoma cells. This study demonstrates that VEGF acts as a survival factor not only for endothelial cells as previously thought, but also for some breast tumour cells, protecting them from apoptosis, particularly under hypoxic stress. The data presented provide an additional rationale for combining anti-VEGF strategies with conventional anti-cancer therapies such as chemotherapy and radiotherapy.
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PMID:Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia. 1809 41

The molecular mechanisms whereby hyperbaric oxygen (HBO) improves ischemic wound healing remain elusive. In this study, a rat model of wound ischemia was used to test the hypothesis that HBO enhances wound healing by modulating hypoxia-inducible factor-1alpha (HIF-1alpha) signaling. Male Sprague-Dawley rats underwent creation of a previously validated ischemic flap. Three groups underwent daily treatment: HBO (90 minutes, 2.4 atm); systemic administration of the free radical scavenger, N-acetylcysteine (NAC 150 mg kg(-1) intraperitoneal); control (neither HBO nor NAC). HBO treatment improved healing of the ischemic wounds. Analysis of ischemic wound tissue extracts demonstrated significantly reduced expression of HIF-1alpha, p53, and BNip3. Additionally, HBO increased expression of Bcl-2 while decreasing cleaved caspase-3. DNA fragmentation was abolished and the number of TUNEL-positive cells was reduced compared to the other groups. Vascular endothelial growth factor, cyclooxygenase-2, and neutrophil infiltration were reduced in ischemic wounds treated with HBO. These results indicate that HBO improves ischemic wound healing by downregulation of HIF-1alpha and subsequent target gene expression with attenuation of cell apoptosis and reduction of inflammation.
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PMID:Hyperbaric oxygen attenuates apoptosis and decreases inflammation in an ischemic wound model. 1833 31

Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis that stimulates proliferation, migration, and metastasis of melanoma. In literature, all studies concerning influences of matrix metalloproteinases (MMPs) and antiapoptotic proteins on VEGF-induced angiogenesis in melanoma patients have been performed in tissue scale in melanoma. The objective of this study was to determine the value of circulating serum VEGF and its possible mechanisms of angiogenesis by circulating VEGF, MMP-3, and Bcl-2 in patients with melanoma. Fifty-one patients with cutaneous melanoma pathologically verified at different stages, and eighteen healthy controls were investigated. Serum VEGF, MMP-3, and Bcl-2 levels were quantitatively analyzed by ELISA. The serum VEGF (P = 0.034) and Bcl-2 (P = 0.005) levels were significantly higher in patients with melanoma than in the control group. However, there was no significant difference in the serum MMP-3 level between melanoma patients and controls (P = 0.51). The serum levels of VEGF were significantly influenced only by Breslow thickness (P = 0.045) and mitosis (0.039) and were not positively correlated with the stage of the disease. Among serum parameters, a significant relationship was found only between serum levels of VEGF and MMP-3 (r = 0.32, P = 0.023). In conclusion, our study demonstrates increased concentrations of VEGF and Bcl-2, but not MMP-3, in serum of melanoma patients regardless of the stage of the disease. VEGF may be a potential endothelial cell growth and survival factor. The mechanism of VEGF regulation of angiogenesis may be in part due to enhanced proliferation and survival of endothelial cells by differential expression of antiapoptotic genes and in part by activation of MMPs.
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PMID:Circulating levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase-3 (MMP-3), and BCL-2 in malignant melanoma. 1836 12

Angiogenesis is a complex process that is regulated by pro- and antiangiogenic factors. These factors can emanate from diverse sources including cancer cells, stromal cells, blood and extracellular matrix. Their relative contribution is likely to change with tumor type and tumor site. Vascular endothelial growth factor (VEGF) is now well confirmed as the primary and the most potent inducer of angiogenesis. To activate cellular signaling pathways, VEGF binds to receptor kinases VEGF-R1, R2 and R3. It then promotes several events required for the formation of new blood vessels, such as endothelial cell survival, proliferation, migration and vascular permeability. Activation of endothelial cells, leads to the secretion of enzymes which degrade the extracellular matrix (ECM) and hence promote metastasis. Similarly it promotes survival by inducing Bcl-2 expression on VEGF receptor positive leukemia. Besides being a potent mitogen for macrovascular cells derived from arteries, veins and lymphatics, it is also highly involved in a number of angiogenic related disorders including inflammatory diseases, rheumatoid arthritis, psoriasis, retinopathies and age related macular degeneration. Neovascularization and increased vessel permeability are being recognized as major causes of VEGF related pathogenesis. Therefore, inhibition of VEGF pathway is a strategy being widely pursued to provide new therapeutics for the treatment of VEGF related disorders. Over twenty compounds with anti-angiogenic properties ranging from VEGF neutralizing antibody, soluble receptors, receptor antagonists or tyrosine kinase inhibitors (TKIs) are either approved or are currently under clinical (phase I - III) study. This review aims to provide an updated account of how VEGF inhibitors are shaping up to become an important class of drugs used in the treatment of cancer.
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PMID:Inhibitors of vascular endothelial growth factor in cancer. 1885 47

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Vascular endothelial growth factor, platelet derived growth factor and the Raf/mitogen-activated protein kinase/extracellular signal regulated kinase (Raf/MEK/ERK) signalling pathway regulates the growth, neovascularization, invasiveness and metastatic potential of HCC. In this study, we investigated the in vivo antitumour activity and mechanisms of action of sorafenib tosylate on four patient-derived HCC xenografts. Sorafenib dosed at 50 mg/kg and 100 mg/kg inhibited tumour growth by 85% and 96%, respectively. Sorafenib-induced growth suppression and apoptosis were associated with inhibition of angiogenesis, down-regulation of phospho-platelet-derived growth factor receptor beta Tyr1021, phospho-eIF4E Ser209, phospho-c-Raf Ser259, c-Raf, Mcl-1, Bcl-2, Bcl-x and positive cell cycle regulators, up-regulation of apoptosis signalling kinase-1, p27 and p21. Expression of IGF-1Rbeta and phosphorylation of c-Raf Ser338, MEK1/2 Ser217/221 and ERK1/2 Thr202/Tyr204 were increased by sorafenib treatment. Phosphorylation of mammalian target-of-rapamycin (mTOR) targets (p70S6K, S6R and 4EBP1) was reduced by sorafenib in sorafenib-sensitive lines but activated in sorafenib-less-sensitive 10-0505 xenograft. Sorafenib-induced phosphorylation of c-met, p70S6K and 4EBP1 was significantly reduced when 10-0505 cells were co-treated with anti-human anti-HGF antibody, suggesting that treatment with sorafenib leads to increased HGF secretion and activation of c-met and mTOR targets. Treatment of 10-0505 tumours with sorafenib plus rapamycin resulted in growth inhibition, inhibition of vascular endothelial growth factor receptor-2 phosphorylation, increased apoptosis and completely blocked sorafenib-induced phosphorylation of mTOR targets and cyclin B1 expression. These data also provide a strong rationale for clinical investigation of sorafenib in combination with mTOR inhibitors in patients with HCC.
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PMID:Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. 1922 May 80

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