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)

Antiangiogenic action of (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-hydroxy-2-methyl-2-dimethoxymethyl-2H-1-benzopyran-4yl)-N'-benzyl guanidine (KR-31372) was examined with its proapoptotic action in human umbilical vein endothelial cells (HUVECs) compared with diazoxide. KR-31372 as well as diazoxide significantly suppressed the neovascularization in mice induced by the Matrigel-containing recombinant human vascular endothelial growth factor (VEGF)165 in vivo and the basal tube formation of HUVECs in vitro with suppression of proliferation of HUVECs stimulated by VEGF165. KR-31372 and diazoxide enhanced DNA fragmentation associated with increase in phosphatase and tensin homolog deleted from chromosome 10 (PTEN) and decrease in serine/threonine kinase phosphorylation, which were accompanied by augmented Bax and cytochrome c release, and suppressed Bcl-2 in HUVECs. In the U87-MG cells, when transfected with expression vectors for sense PTEN, KR-31372 enhanced DNA fragmentation, but not in naive U87-MG cells. The suppression by KR-31372 and diazoxide of these variables was significantly antagonized by 5-hydroxydecanoic acid, a mitochondrial KATP channel blocker. Taken together, KR-31372 strongly inhibited angiogenesis in HUVECs by proapoptotic mechanism via mediation of 5-hydroxydecanoic acid-inhibitable mitochondrial KATP channel opening and PTEN phosphorylation.
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PMID:Antiangiogenic effect of KR-31372 by apoptosis via mediation of mitochondrial KATP channel opening and the phosphatase and tensin homolog deleted from chromosome 10 phosphorylation. 1262 42

Vascular insufficiency and retinal ischemia precede many proliferative retinopathies and stimulate secretion of various vasoactive growth factors, including vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). It is unclear, however, how PlGF, which is elevated in proliferative diabetic retinopathy and is a VEGF homolog that binds only to VEGF receptor (VEGFR)-1, promotes pathological angiogenesis. When primary microvascular endothelial cells were grown on collagen gels, PlGF-containing ligands upregulated Bcl-2 expression and stimulated the formation of capillary-like tube networks that were retained for up to 14 days in culture. The inhibition of VEGFR-1 results in a dramatic decrease in the number of capillary connections, indicating that VEGFR-1 ligands promote branching angiogenesis. In contrast, VEGF-induced tube formations and Bcl-2 expression were significantly decreased at the end of this period. Flow cytometry analysis of annexin-V/propidium iodide-stained cells revealed that PlGF and PlGF/VEGF heterodimer inhibited apoptosis in serum-deprived endothelial cells. These two growth factors stimulated a survival signaling pathway phosphatidylinositol 3-kinase (PI3K), as identified by increased Akt phosphorylation and because blocking PI3K signalling by adenovirus-mediated overexpression of wild-type phosphatase and tensin homolog on chromosome 10 (PTEN) disrupted angiogenesis and decreased Bcl-2 expression by PlGF and PlGF/VEGF heterodimer, whereas a dominant-negative PTEN mutant enhanced endothelial sprout formation and Bcl-2 expression. Together, these findings indicate that PlGF-containing ligands contribute to pathological angiogenesis by prolonging cell survival signals and maintaining vascular networks.
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PMID:Activation of vascular endothelial growth factor receptor-1 sustains angiogenesis and Bcl-2 expression via the phosphatidylinositol 3-kinase pathway in endothelial cells. 1463 57

This study shows the in vivo neuroprotective effect of cilostazol against cerebral ischemic injury evoked by subjecting rats to 2-h occlusion of middle cerebral artery (MCAO) followed by 24-h reperfusion. We observed the signaling pathway by which cilostazol suppressed MCAO-induced increased phosphorylation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) and apoptosis via increased phosphorylation of casein kinase 2 (CK2). When rats received 30 mg/kg cilostazol orally two times at 5 min and 4 h after the completion of ischemia, the infarct area was significantly reduced in the cortex and striatum with improvement of neurological deterioration. Increased DNA fragmentation in the penumbral zone was significantly reduced by cilostazol. Cilostazol significantly elevated phosphorylation levels of CK2, Akt, and cyclic AMP response element-binding protein (CREB) in association with increased Bcl-2 in the ischemic area, whereas the elevated PTEN phosphorylation was significantly reduced, all of which were antagonized by iberiotoxin, a maxi-K channel blocker, administered intracisternally 30 min before ischemia. In conclusion, cilostazol ameliorates the neuronal damage by suppression of apoptotic cell death via the maxi-K channel opening-coupled up-regulation of CK2 phosphorylation and down-regulation of PTEN phosphorylation with resultant increase in the Akt and CREB phosphorylation and increased Bcl-2 protein.
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PMID:Cilostazol prevents focal cerebral ischemic injury by enhancing casein kinase 2 phosphorylation and suppression of phosphatase and tensin homolog deleted from chromosome 10 phosphorylation in rats. 1463 32

This study shows the signaling pathway by which (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378) prevents tumor necrosis factor (TNF)-alpha-induced neuronal cell death. KR-31378 restored TNF-alpha-induced decreased cell viability of SK-N-SH. U87-MG cells (PTEN-null glioblastoma cell line) transfected with expression vectors for sense PTEN (phosphatase and tensin homolog deleted from chromosome 10) showed significantly decreased cell viability, which was restored by KR-31378. TNF-alpha-induced increased PTEN phosphorylation and decreased phosphorylation of Akt/cyclic AMP response element-binding protein (CREB) in SK-N-SH cells were concentration-dependently reversed by KR-31378, those of which were antagonized by iberiotoxin, a maxi-K channel blocker. TNF-alpha and apigenin, a casein kinase2 (CK2) inhibitor, showed decreased CK2 phosphorylation and increased PTEN phosphorylation, which were reversed by KR-31378. KR-31378 increased K(+) currents by activating the maxi-K channels in SK-N-SH cells, with suppression of TNF-alpha-induced increase in cytosolic Ca(2+) and elevation of suppressed mitochondrial membrane potential, all of which were antagonized by iberiotoxin. It is suggested that increase in cell viability by KR-31378 is ascribed to the maxi-K channel opening-coupled upregulation of CK2/Akt/CREB phosphorylation and downregulation of PTEN phosphorylation in association with increased Bcl-2 and decreased Bax levels.
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PMID:Anti-apoptotic action of (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378) by suppression of the phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and increased phosphorylation of casein kinase2/Akt/ cyclic AMP response element binding protein via maxi-K channel opening in neuronal cells. 1533 44

This study aimed to assess the signaling pathway of the neuroprotective action of estrogen in the cerebral ischemic injury evoked by subjecting rats to 2-h occlusion of the middle cerebral artery (MCA) followed by 24-h reperfusion. Rats received 17 beta-estradiol (1, 4 and 10 mg/kg, i.p.) 24 h before and 5 min after the completion of 2-h MCA occlusion. The cerebral infarct area was consistently observed in the cortex and striatum of the left hemisphere. Increased terminal deoxynucleotidyl transferase-mediated deoxyuridine-biotin nick-end labeling (TUNEL)-positive cells and DNA fragmentation in the penumbral zone were significantly reduced by 17 beta-estradiol. In line with these results, 17 beta-estradiol significantly increased Akt and cyclic AMP response element binding protein (CREB) with increased Bcl-2 protein in the ischemic area, whereas the elevated the phosphatase and tensin homolog deleted from chromosome10 (PTEN) phosphorylation was significantly reduced with decreased Bax protein and cytochrome c release. Inhibition of DNA fragmentation, PTEN phosphorylation, and Akt activation by 17 beta-estradiol were antagonized by iberiotoxin, a maxi-K channel blocker. Taken together, it is suggested that suppression of cerebral ischemic injury by 17 beta-estradiol may be ascribed to the maxi-K channel opening-coupled downregulation of PTEN phosphorylation and upregulation of Akt and CREB phosphorylation with resultant increase in Bcl-2 protein and decrease in Bax protein and cytochrome c release.
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PMID:17 Beta-estradiol prevents focal cerebral ischemic damages via activation of Akt and CREB in association with reduced PTEN phosphorylation in rats. 1548 76

We have previously shown that low extracellular pH (pHe) promotes cell killing by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In this study, we examined whether amiloride, an inhibitor of the Na(+)/H(+) antiporter capable of lowering the intracellular pH (pHi), can potentiate TRAIL-induced apoptotic death. Human prostate adenocarcinoma DU-145 cells were treated with various concentrations of TRAIL (10-200 ng/ml) and/or amiloride (0.1-1 mM) for 4 h. Amiloride, which caused little or no cytotoxicity by itself, enhanced TRAIL-induced apoptosis. The TRAIL-mediated activation of caspase, and PARP (poly (ADP-ribose) polymerase) cleavage were both promoted by amiloride. Western blot analysis showed that combined treatment with TRAIL and amiloride did not change the levels of TRAIL receptors (death receptor (DR)4, DR5, and DcR2 (decoy recepter 2) or antiapoptotic proteins (FLICE-inhibitory protein (FLIP), inhibitor of apoptosis (IAP), and Bcl-2). However, unlike pHe, amiloride promoted the dephosphorylation of Akt. Interestingly, amiloride also induced the dephosphorylation of P13K (phosphatidylinositol 3-kinase) and PDK-1 (phosphoinositide-dependent kinase-1) kinases along with PTEN (phosphatase and tensin homolog deleted on chromosome 10) and PP1alpha phosphatases. In vitro kinase assays revealed that amiloride inhibited phosphorylation of kinases and phosphatases by competing with ATP. Taken together, the present studies suggest that amiloride enhances TRAIL-induced cytotoxicity by inhibiting phosphorylation of the PI3K-Akt pathway-associated kinases and phosphatases.
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PMID:Amiloride augments TRAIL-induced apoptotic death by inhibiting phosphorylation of kinases and phosphatases associated with the P13K-Akt pathway. 1555 24

The resistance of prostate cancers to radiation therapy has been linked to abnormalities in overexpression of Bcl-2, an oncogene associated with inhibition of apoptosis. In this study, we evaluated whether the combination of the overexpression of phosphatase and tensin homolog (PTEN), a protein known to inhibit Bcl-2 expression, and radiation therapy would inhibit proliferation of Bcl-2-expressing human prostate cancer cells inoculated into the subcutis of athymic mice. Compared with either treatment alone, the combination of adenoviral vector-expressed PTEN (AdPTEN) and radiation (5 Gy) significantly inhibited xenograft tumor growth. Median tumor size on day 48 was 1030 mm3 in untreated controls, 656 mm3 in mice treated with radiation (5 Gy) alone, 640 mm3 in mice treated with AdPTEN alone, and 253 mm3 in mice treated with the combination (p<0.001). Treatment was well tolerated in all cases. Combination treatment also enhanced apoptosis (p=0.048), inhibited cellular proliferation (p=0.005), and inhibited tumor-induced neovascularity (p=0.030). Interestingly, this treatment increased apoptosis not only in tumor cells but also in tumor-associated endothelial cells. Together, these findings indicate that AdPTEN strongly inhibits the growth of human prostate tumors, especially when combined with radiation therapy, and that this effect is mediated by the induction of apoptosis and by the inhibition of angiogenesis and cellular proliferation.
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PMID:Combination of PTEN gene therapy and radiation inhibits the growth of human prostate cancer xenografts. 1698 24

Our previous studies have shown that dietary pigment curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1-6-heptadine-3,5-dione; C21H20O6] sensitizes human prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L)-induced apoptosis by inhibiting nuclear factor (NF)-kappaB. In the present study, we demonstrate that activated (phosphorylated) Akt kinase plays a pivotal role in regulation of NF-kappaB and sensitization of LNCaP and PC3 prostate cancer cells to TRAIL by curcumin. Curcumin inhibited the expression of phospho-Akt (p-Akt), which was not due to activation of phosphatase and tensin homolog deleted on chromosome 10 phosphatase activity by curcumin. Because NF-kappaB is a downstream target of Akt, we investigated whether inhibition of NF-kappaB by curcumin is mediated through suppression of p-Akt. Data demonstrate that treatment of PC3 cells with SH-6 (JAm Chem Soc 125:1144-1145, 2003), a specific inhibitor of Akt, or transfection with small inhibitory RNA (siRNA)-Akt not only inhibited p-Akt but also abrogated the expression and transcriptional activity of NF-kappaB. Furthermore, overexpression of constitutively active Akt1 in cancer cells prevented the inhibition of NF-kappaB by curcumin. In addition, treatment with SH-6 or transfection with siRNA-Akt sensitized PC3 cells to TRAIL-induced cytotoxicity. On the other hand, SH-6 does not inhibit NF-kappaB or sensitize DU145 cancer cells to TRAIL because these cells do not express p-Akt. Because expression of antiapoptotic Bcl-2, Bcl-xL, and X-chromosome-linked inhibitor of apoptosis protein (XIAP) is regulated by NF-kappaB, both curcumin and SH-6 decreased the levels of these proteins in PC3 cells through inhibition of NF-kappaB. Furthermore, gene silencing of Bcl-2 with siRNA-Bcl-2 sensitized PC3 cells to TRAIL. Collectively, these data define a pathway whereby curcumin sensitizes prostate cancer cells to TRAIL by inhibiting Akt-regulated NF-kappaB and NF-kappaB-dependent antiapoptotic Bcl-2, Bcl-xL, and XIAP.
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PMID:Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1-6-heptadine-3,5-dione; C21H20O6] sensitizes human prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L-induced apoptosis by suppressing nuclear factor-kappaB via inhibition of the prosurvival Akt signaling pathway. 1728 36

In recent years, the phosphoinositide-3-kinase/Akt cell survival signaling pathway has been increasingly researched in the field of stroke. Akt activity is suggested to be upregulated by phosphorylation through the activation of receptor tyrosine kinases by growth factors. Although the upstream signaling components phosphoinositide-dependent protein kinase (PDK)1 and integrinlinked kinase enhance the activity of Akt, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) decreases it. Upon activation, Akt phosphorylates an array of molecules, including glycogen synthase kinase3beta (GSK3beta), forkhead homolog in rhabdomyosarcoma (FKHR), and Bcl-2-associated death protein, thereby blocking mitochondrial cytochrome c release and caspase activity. Generally, the level of Akt phosphorylation at site Ser 473 (P-Akt) transiently increases after focal ischemia, whereas the levels of phosphorylation of PTEN, PDK1, forkhead transcription factor, and GSK3beta decrease. Numerous compounds (such as growth factors, estrogen, free radical scavengers, and other neuroprotectants) reduce ischemic damage, possibly by upregulating P-Akt. However, preconditioning and hypothermia block ischemic damage by inhibiting an increase of P-Akt. Inhibition of the Akt pathway blocks the protective effect of preconditioning and hypothermia, suggesting the Akt pathway contributes to their protective effects and that the P-Akt level does not represent its true kinase activity. Together, attenuation of the Akt pathway dysfunction contributes to neuronal survival after stroke.
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PMID:Phosphoinositide-3-kinase/akt survival signal pathways are implicated in neuronal survival after stroke. 1730 56

Curcumin (diferulolylmethane), an active ingredient derived from the rhizome of the plant Curcuma longa, has anticancer activity in vitro and in vivo. Although curcumin possesses chemopreventive properties against several types of cancer, the molecular mechanisms by which it inhibits cell growth and induces apoptosis are not clearly understood. Our data revealed that curcumin inhibited growth and induced apoptosis in androgen-dependent and -independent prostate cancer cells, but had no effect on normal human prostate epithelial cells. Curcumin downregulated the expression of Bcl-2, and Bcl-XL and upregulated the expression of p53, Bax, Bak, PUMA, Noxa, and Bim. Curcumin upregulated the expression of p53 as well as its phosphorylation at serine 15, and acetylation in a concentration-dependent manner. Acetylation of histone H3 and H4 was increased in cells treated with curcumin, suggesting histone modification may regulate gene expression. Treatment of LNCaP cells with curcumin resulted in translocation of Bax and p53 to mitochondria, production of reactive oxygen species, drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and induction of apoptosis. Furthermore, curcumin inhibited expression of phosphatidyl-inositol-3 kinase (PI3K) p110 and p85 subunits, and phosphorylation of Ser 473 AKT/PKB. Downregulation of AKT by inhibitors of PI3K (Wortmannin and LY294002) and AKT, or by dominant negative AKT increased curcumin-induced apoptosis, whereas transfection of constitutively active AKT attenuated this effect. Similarly, wild-type phosphatase and tensin homolog deleted from chromosome 10 (PTEN) enhanced curcumin-induced apoptosis and, in contrast, inactive PTEN (G129E and G129R) inhibited curcumin-induced apoptosis. Overexpression of constitutively active AKT inhibited curcumin-induced p53 translocation to mitochondria, and Smac release to cytoplasm, whereas inhibition of AKT by dominant negative AKT enhanced curcumin-induced p53 translocation to mitochondria and Smac release. Our study establishes a role for AKT in modulating the direct action of p53 on the caspase-dependent mitochondrial death pathway and suggests that these important biological molecules interact at the level of the mitochondria to influence curcumin sensitivity. These properties of curcumin strongly suggest that it could be used as a cancer chemopreventive agent.
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PMID:Involvement of Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer. 1733 30


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