Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Garcinol, a polyisoprenylated benzophenone, from the Garcinia indica fruit rind, has been suggested to be an anti-inflammatory and anti-cancer agent. To explore the possible use of this redox-sensitive compound as a colon cancer preventive agent, we investigated the effects of garcinol and its oxidative derivatives, cambogin, garcim-1, and garcim-2, on the growth of HT-29 and HCT-116 colon cancer cells, as well as IEC-6 and INT-407 normal immortalized intestinal cells. Garcinol and its derivatives showed potent growth-inhibitory effects on all intestinal cells, showing IC50 of 3.2-21.4 microM after a 3-day treatment. Garcim-1 exhibited the strongest effect with IC50 of 3.2-5.9 microM. Garcinol was more effective in inhibiting growth of cancer cells than that of normal immortalized cells. Flow-cytometric analysis showed increased sub-G1 cells by treatment with garcinol and cambogin. Induction of apoptosis by garcinol and cambogin (2-10 microM) was also observed based on caspase-3 activation and enhanced annexin V staining. The inhibitory effect of garcinol on cell growth was much more pronounced in the absence of fetal bovine serum (FBS), decreasing IC50 to 1.5 from 11.8 microM in 72-h incubations and to 3 from 38 microM in 24-h incubations, possibly due to the binding of garcinol to FBS, which markedly reduced cellular levels of garcinol. Under these conditions, redox reactions seem not to be involved in the inhibition. In contrast to the inhibitory effect, low concentrations (<1 microM) of garcinol and cambogin stimulated the growth of both normal and cancer cells by 10-100%, and the activity seemed to be mediated by reactive oxygen species. In the presence of superoxide dismutase/catalase or N-acetyl cysteine, low concentrations of garcinol (<1 microM) decreased cell growth. Garcinol (0.5-1 microM) also increased the phosphorylation of extracellular signal-related kinase 1/2 and AKT and the level of survivin, and the effects were abolished in the presence of superoxide dismutase/catalase. Our results indicate that garcinol and its derivatives can inhibit intestinal cell growth, but low concentrations of garcinol can stimulate cell growth. It remains to be determined whether the currently observed stimulatory and inhibitory effects of garcinol on colon cell growth occur in vivo.
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PMID:Effects of garcinol and its derivatives on intestinal cell growth: Inhibitory effects and autoxidation-dependent growth-stimulatory effects. 1738 2

The aim of this study is to investigate the expression of CXCR4 receptor in cervical adenocarcinoma and related mechanisms involved in pelvic lymph node metastasis. Immunohistochemistry was used to evaluate the expression of CXCR4 and the association of pelvic lymph node metastasis in archived tissue from clinical stage IB cervical adenocarcinomas (n = 37) and from benign specimens obtained at hysterectomy for other causes (n = 48). The HeLa cell (cervical adenocarcinoma-derived cell) line that expresses CXCR4 was used to study the interaction between the CXCR4 receptor and stromal cell-derived factor 1alpha (SDF-1alpha). Cell migration assays, cell numbers, flow cytometry, cell proliferation assay, and western blot were used to study the function of CXCR4 and its downstream signal transduction. The positive cases were semiquantitatively divided into three score classes according to their staining. Tumors with strong CXCR4 stainings were more likely to have pelvic lymph node metastasis than those with weak or negative stainings (87.5% vs 34.5%; P = 0.014). Only 25% of the benign specimens had weak or negative staining for CXCR4. Functioning CXCR4 receptor was expressed on HeLa cells. SDF-1alpha provoked significant signal transduction events, including chemotaxis and rescue from apoptosis. These actions were apparently mediated by the activation and phosphorylation of the extracellular signal-regulated kinase 1/2 and AKT pathways. We conclude CXCR4 expression is associated with cervical adenocarcinoma cell migration and proliferation, and primary cervical adenocarcinoma cells expressing CXCR4 are significantly more likely to metastasize to pelvic lymph nodes.
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PMID:CXCR4 expression is associated with pelvic lymph node metastasis in cervical adenocarcinoma. 1750 81

Rituximab (chimeric anti-CD20 monoclonal antibody) is the first Food and Drug Administration approved antitumor antibody and is used in the treatment of B-non-Hodgkin's lymphoma (B-NHL). It is used as single monotherapy or in combination with chemotherapy and has improved the treatment outcome of patients with B-NHL. The in vivo mechanisms of rituximab-mediated antitumor effects include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cell cytotoxicity (CDC), growth-inhibition and apoptosis. A subset of patients does not initially respond to rituximab and several responsive patients develop resistance to further rituximab treatment. The mechanism of rituximab unresponsiveness is not known. Besides the above-postulated mechanisms, rituximab has been shown to trigger the cells via CD-20. Studies performed with B-NHL cell lines as model systems revealed several novel mechanisms of rituximab-mediated effects that are involved in chemo/immunosensitization and the development of resistance to rituximab. Rituximab has been shown to inhibit the p38 mitogen-activated protein kinase, nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated kinase 1/2 (ERK 1/2) and AKT antiapoptotic survival pathways, all of which result in upregulation of phosphatase and tensin homolog deleted on chromosome ten and Raf kinase inhibitor protein and in the downregulation of antiapoptotic gene products (particularly Bcl-2, Bcl-(xL) and Mcl-1), and resulting in chemo/immunosensitization. Further, rituximab treatment inhibits the overexpressed transcription repressor Yin Yang 1 (YY1), which negatively regulates Fas and DR5 expression and its inhibition leads to sensitization to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Rituximab-resistant clones were generated as model to examine the mechanism of in vivo rituximab unresponsiveness. These clones showed reduced expression of CD20 and hyperactivation of the above antiapoptotic signaling pathways and failure of rituximab to trigger the cells leading to inhibition of ADCC, CDC and chemo/immunosensitization. Interference with the hyperactivated pathways with various pharmacological and proteasome inhibitors reversed resistance. Furthermore, the above findings have identified several gene products that can serve as new prognostic/diagnostic biomarkers as well as targets for therapeutic intervention in B-NHL.
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PMID:Rituximab-induced inhibition of antiapoptotic cell survival pathways: implications in chemo/immunoresistance, rituximab unresponsiveness, prognostic and novel therapeutic interventions. 1753 16

Insulin-like growth factor-I receptor (IGF-IR) and its ligands, IGF-I and IGF-II, are up-regulated in a variety of human cancers. In tumors, such as colorectal, non-small cell lung, ovarian, and pediatric cancers, which may drive their own growth and survival through autocrine IGF-II expression, the role of IGF-IR is especially critical. Here, we present a novel small-molecule IGF-IR kinase inhibitor, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP), which displayed a cellular IC(50) of 19 nmol/L for inhibition of ligand-dependent autophosphorylation of human IGF-IR with 14-fold cellular selectivity relative to the human insulin receptor. PQIP showed minimal activity against a panel of 32 other protein kinases. It also abolished the ligand-induced activation of downstream phosphorylated AKT and phosphorylated extracellular signal-regulated kinase 1/2 in both IGF-IR transfectant cells and a GEO human colorectal cancer cell line. Analysis of GEO cells revealed a significant level of both phosphorylated IGF-IR and IGF-II expression. Furthermore, inactivation of IGF-II in conditioned GEO culture medium by a neutralizing antibody diminished IGF-IR activation, indicating the presence of a functional IGF-II/IGF-IR autocrine loop in GEO cells. Once daily oral dosing of PQIP induced robust antitumor efficacy in GEO xenografts. The antitumor efficacy correlated with the degree and duration of inhibition of tumor IGF-IR phosphorylation in vivo by this compound. Moreover, when mice were treated for 3 days with a dose of PQIP that maximally inhibited tumor growth, only minor changes in blood glucose were observed. Thus, PQIP represents a potent and selective IGF-IR kinase inhibitor that is especially efficacious in an IGF-II-driven human tumor model.
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PMID:A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor dependent tumor growth in vivo. 1767 Oct 83

Monotherapies have proven largely ineffective for the treatment of glioblastomas, suggesting that increased patient benefit may be achieved by combining therapies. Two protumorigenic pathways known to be active in glioblastoma include RAS/RAF/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT/target of rapamycin (TOR). We investigated the efficacy of a combination of novel low molecular weight inhibitors LBT613 and RAD001 (everolimus), which were designed to target RAF and TOR, respectively. LBT613 decreased phosphorylation of extracellular signal-regulated kinase 1 and 2, downstream effectors of RAF, in a human glioma cell line. RAD001 resulted in decreased phosphorylation of the TOR effector S6. To determine if targeting RAF and TOR activities could result in decreased protumorigenic glioma cellular behaviors, we evaluated the abilities of LBT613 and RAD001 to affect the proliferation, migration, and invasion of human glioma cells. Treatment with either LBT613 or RAD001 alone significantly decreased the proliferation of multiple human glioma cell lines. Furthermore, LBT613 and RAD001 in combination synergized to decrease glioma cell proliferation in association with G(1) cell cycle arrest. Glioma invasion is a critical contributor to tumor malignancy. The combination of LBT613 and RAD001 inhibited the invasion of human glioma cells through Matrigel to a greater degree than treatment with either drug alone. These data suggest that the combination of LBT613 and RAD001 reduces glioma cell proliferation and invasion and support examination of the combination of RAF and TOR inhibitors for the treatment of human glioblastoma patients.
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PMID:The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion. 1776 37

Loss of SEMA3F occurs frequently in lung cancer and correlates with advanced stage of disease. We previously reported that SEMA3F blocked tumor formation by H157 lung cancer cells in a rat orthotopic model. This was associated with loss of activated alpha(V)beta(3) integrin, impaired cell adhesion to extracellular matrix components, and down-regulation of phospho-extracellular signal-regulated kinase 1/2 (ERK1/2). These results suggested that SEMA3F might interfere with integrin outside-in signaling. In the present report, we found that SEMA3F decreased adhesion to vitronectin, whereas integrin-linked kinase (ILK) kinase activity was down-regulated in SEMA3F-expressing H157 cells. Exposure to SEMA3F-conditioned medium led to diminution of phospho-ERK1/2 in four of eight lung cancer cell lines, and ILK silencing by small interfering RNA led to similar loss of phospho-ERK1/2 in H157 cells. Moreover, SEMA3F expression (with constitutive and inducible systems) also reduced AKT and signal transducer and activator of transcription 3 (STAT3) phosphorylation independently of ILK-ERK1/2. These signaling changes extended downstream to hypoxia-inducible factor-1alpha (HIF-1alpha) protein and vascular endothelial growth factor (VEGF) mRNA levels, which were both reduced in three of four SEMA3F-transfected cell lines. Mechanistically, the effects on HIF-1alpha were consistent with inhibition of its AKT-driven protein translation initiation, with no effect on HIF-1alpha mRNA level or protein degradation. Furthermore, when H157 cells were injected s.c. in nude mice, tumors derived from SEMA3F-expressing cells showed lower microvessel density and tumor growth. These results show that SEMA3F negatively affects ILK-ERK1/2 and AKT-STAT3 signaling, along with inhibition of HIF-1alpha and VEGF. These changes would be anticipated to contribute significantly to the observed antitumor activity of SEMA3F.
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PMID:Semaphorin SEMA3F affects multiple signaling pathways in lung cancer cells. 1787 11

The oxygen sensitive alpha-subunit of the hypoxia-inducible factor-1 (HIF-1) is a major trigger of the cellular response to hypoxia. Although the posttranslational regulation of HIF-1alpha by hypoxia is well known, its transcriptional regulation by hypoxia is still under debate. We, therefore, investigated the regulation of HIF-1alpha mRNA in response to hypoxia in pulmonary artery smooth muscle cells. Hypoxia rapidly enhanced HIF-1alpha mRNA levels and HIF-1alpha promoter activity. Furthermore, inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT but not extracellular signal-regulated kinase 1/2 pathway blocked the hypoxia-dependent induction of HIF-1alpha mRNA and HIF-1alpha promoter activity, suggesting involvement of a PI3K/AKT-regulated transcription factor. Interestingly, hypoxia also induced nuclear factor-kappaB (NFkappaB) nuclear translocation and activity. In line, expression of the NFkappaB subunits p50 and p65 enhanced HIF-1alpha mRNA levels, whereas blocking of NFkappaB by an inhibitor of nuclear factor-kappaB attenuated HIF-1alpha mRNA induction by hypoxia. Reporter gene assays revealed the presence of an NFkappaB site within the HIF-1alpha promoter, and mutation of this site abolished induction by hypoxia. In line, gel shift analysis and chromatin immunoprecipitation confirmed binding of p50 and p65 NFkappaB subunits to the HIF-1alpha promoter under hypoxia. Together, these findings provide a novel mechanism in which hypoxia induces HIF-1alpha mRNA expression via the PI3K/AKT pathway and activation of NFkappaB.
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PMID:Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells. 1789 80

We demonstrate that a proteoglycan decorin (DCN) up-regulates the vascular endothelial growth factor (VEGF) expression with activation of VEGF regulating transcription factors Sp1, hypoxia-inducible factor 1alpha (HIF1alpha), and signal transducer and activator of transcription 3 (Stat3) via epidermal growth factor receptor (EGFR), mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2), and protein kinase B (AKT) pathways in DCN transfected mouse cerebral endothelial (MCE) cells. Treatment with pharmacological inhibitors and small interfering RNAs reveal that induction and activation of Sp1, HIF1alpha, and Stat3 facilitate their nuclear localization and binding to their specific motifs of the VEGF promoter and induce VEGF expression via two independent pathways, DCN/EGFR/phosphoinositide-3 kinase/AKT and DCN/EGFR/ERK1/2, respectively, in DCN synthesizing MCE cells. The cell type specific glycosylation protects Sp1 and HIF1alpha from proteosome degradation and plays an important and novel role in the regulation of VEGF in DCN transfected MCE cells. Induction of gelatinases (matrix metalloproteinase 2 and 9), the serine protease tissue plasminogen activator and plasmin by DCN transfection in MCE cells leads to extracellular proteolysis and to release of matrix-bound VEGF and activation of angiogenesis. In this study, we demonstrate that two independent downstream signal pathways, DCN/EGFR/ERK1/2 and DCN/EGFR/phosphoinositide-3 kinase/AKT, mediate up-regulation and activation of transcription factors of VEGF such as HIF1alpha, Stat3, and Sp1 and increase VEGF transcription and angiogenesis in MCE cells.
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PMID:Ectopic decorin expression up-regulates VEGF expression in mouse cerebral endothelial cells via activation of the transcription factors Sp1, HIF1alpha, and Stat3. 1802 Dec 92

The present studies have determined whether interactions between the cyclin-dependent kinase inhibitor flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat; Zolinza) occur in breast cancer cells. MDA-MB-231 and MCF7 cells were treated with flavopiridol (25-100 nmol/L) and vorinostat (125-500 nmol/L) in vitro, and mechanisms of cell killing were determined. Concurrent treatment of cells with flavopiridol and vorinostat or treatment of cells with flavopiridol followed by vorinostat promoted cell killing in a greater than additive fashion. Similar data were obtained with the CDK inhibitor roscovitine. Flavopiridol suppressed c-FLIP-l/s and BCL-xL expression, whereas vorinostat reduced expression of BCL-xL, and combined exposure to flavopiridol and vorinostat reduced MCL-1 and X-chromosome-linked inhibitor of apoptosis protein (XIAP) levels. Pharmacologic or genetic inhibition of caspase-8 reduced flavopiridol toxicity, but abolished killing by vorinostat and cell death caused by the vorinostat/flavopiridol regimen. Loss of BAX/BAK function or loss of BID function modestly reduced flavopiridol toxicity, but abolished vorinostat-mediated potentiation of flavopiridol toxicity, as did inhibition of caspase-9. Inhibition and/or deletion of cathepsin B function significantly attenuated vorinostat/flavopiridol lethality. Flavopiridol suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT activity and expression of activated forms of AKT and mitogen-activated protein/ERK kinase 1 maintained c-FLIP-l/s, BCL-xL, and XIAP expression and protected cells against flavopiridol/vorinostat lethality. Overexpression of c-FLIP-s and BCL-xL abolished the lethality of flavopiridol/vorinostat. Collectively, these data argue that flavopiridol enhances the lethality of vorinostat in breast cancer cells in part through the inhibition of AKT and ERK1/2 function, leading to reduced expression of multiple inhibitors of the extrinsic and intrinsic apoptosis pathways, as well as activation of cathepsin protease-dependent pathways.
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PMID:Extrinsic pathway- and cathepsin-dependent induction of mitochondrial dysfunction are essential for synergistic flavopiridol and vorinostat lethality in breast cancer cells. 1806 90

The present studies defined the biological effects of a GST fusion protein of melanoma differentiation-associated gene-7 (mda-7), GST-MDA-7 (1 and 30 nmol/L), on cell survival and cell signaling in primary human glioma cells in vitro. GST-MDA-7, in a dose- and time-dependent fashion killed glioma cells with diverse genetic characteristics; 1 nmol/L caused arrest without death, whereas 30 nmol/L caused arrest and killing after exposure. Combined inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT function was required to enhance 1 nmol/L GST-MDA-7 lethality in all cell types, whereas combined activation of MEK1 and AKT was required to suppress 30 nmol/L GST-MDA-7 lethality; both effects are mediated in part by modulating c-Jun NH(2)-terminal kinase (JNK) 1-3 activity. The geldanamycin 17AAG inhibited AKT and ERK1/2 in GBM cells and enhanced GST-MDA-7 lethality. JNK1-3 signaling promoted BAX activation and mitochondrial dysfunction. In GBM6 cells, GST-MDA-7 (30 nmol/L) transiently activated p38 mitogen-activated protein kinase, which was modestly protective against JNK1-3-induced toxicity, whereas GST-MDA-7 (300 nmol/L) caused prolonged intense p38 mitogen-activated protein kinase activation, which promoted cell death. In GBM12 cells that express full-length mutant activated ERBB1, inhibition of ERBB1 did not modify GST-MDA-7 lethality; however, in U118 established glioma cells, stable overexpression of wild-type ERBB1 and/or truncated active ERBB1vIII suppressed GST-MDA-7 lethality. Our data argue that combined inhibition of ERK1/2 and AKT function, regardless of genetic background, promotes MDA-7 lethality in human primary human glioma cells via JNK1-3 signaling and is likely to represent a more ubiquitous approach to enhancing MDA-7 toxicity in this cell type than inhibition of ERBB1 function.
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PMID:Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling. 1828 16


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