Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pleckstrin homology domain-interacting protein (PHIP) was originally identified as a 902-amino-acid (aa) protein that regulates insulin receptor-stimulated GLUT4 translocation in skeletal-muscle cells. Immunoblotting and immunohistological analyses of pancreatic beta-cells reveal prominent expression of a 206-kDa PHIP isoform restricted to the nucleus. Herein, we report the cloning of this larger, 1,821-aa isoform of PHIP (PHIP1), which represents a novel WD40 repeat-containing protein. We demonstrate that PHIP1 overexpression stimulates insulin-like growth factor 1-dependent and -independent proliferation of beta-cells, an event which correlates with transcriptional upregulation of the cyclin D2 promoter and the accumulation of cyclin D2 protein. RNA interference knockdown of PHIP1 in INS-1 cells abrogates insulin receptor substrate 2 (IRS2)-mediated DNA synthesis, providing for a specific role for PHIP1 in the enhancement of IRS2-dependent signaling responses leading to beta-cell growth. Finally, we provide evidence that PHIP1 overexpression blocks free fatty acid-induced apoptosis in INS-1 cells, which is accompanied by marked activation of phosphoprotein kinase B (PKB)/AKT and the concomitant inhibition of caspase-9 and caspase-3 cleavage. Our finding that the restorative effect of PHIP1 on beta-cell lipotoxicity can be attenuated by the overexpression of dominant-negative PKB suggests a key role for PKB in PHIP1-mediated cytoprotection. Taken together, these findings provide strong support for PHIP1 as a novel positive regulator of beta-cell function. We suggest that PHIP1 may be involved in the induction of long-term gene expression programs to promote beta-cell mitogenesis and survival.
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PMID:Identification of a WD40 repeat-containing isoform of PHIP as a novel regulator of beta-cell growth and survival. 1763 24

MAP17 is a non-glycosylated membrane-associated protein that has been shown to be over-expressed in human carcinomas, suggesting a possible role of this protein in tumorigenesis. However, very little is known about the molecular mechanism mediating the possible tumor promoting properties of MAP17. To analyze the effect of MAP17 on cell survival, we used Rat1 fibroblasts model where Myc over-expression promotes apoptosis in low serum conditions. In the present work, we report that over-expression of MAP17 protects Rat1a fibroblasts from Myc-induced apoptosis through reactive oxygen species (ROS)-mediated activation of the PI3K/AKT signaling pathway. MAP17-mediated survival was associated with absence of Bax translocation to the mitochondria and reduced caspase-3 activation. We show that a fraction of PTEN undergoes oxidation in MAP17-over-expressing cells. Furthermore, activation of AKT by MAP17 as measured by Thr308 phosphorylation was independent of PI3K activity. Importantly, modulation of ROS by antioxidant treatment prevented activation of AKT, restoring the level of apoptosis in serum-starved Rat1/c-Myc fibroblasts. Finally, over-expression of a dominant-negative mutant of AKT in MAP17-expressing clones makes them sensitive to serum depletion. Our data indicate that MAP17 protein activates AKT through ROS and this is determinant to confer resistance to Myc-induced apoptosis in the absence of serum.
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PMID:MAP17 inhibits Myc-induced apoptosis through PI3K/AKT pathway activation. 1767 38

Several indole ethyl isothiocyanate (IEITC) analogs were designed, synthesized, and screened to evaluate their cytotoxicity against neuroblastoma (NB) cells in-vitro. In NB, predominantly a tumor of early childhood, survival remains low despite aggressive treatments. Therefore, novel treatment strategies are greatly needed. The objective of the present study was to study the therapeutic potential of IEITC by analyzing the cytotoxic, anti-proliferative, and apoptotic effects on NB cell lines. 7-Methyl-indole-3-ethyl isothiocyanate (7Me-IEITC) proved to be cytotoxic to various NB cell lines (SMS-KCNR, SK-N-SH, SH-SY5Y, and IMR-32) with an IC(50) at 2.5-5.0 microM, while primary control cells (lung fibroblasts) were not affected. 7Me-IEITC led to the activation of apoptotic markers caspase-3, -8, and -9, caused activation of pro-apoptotic p38 MAPK and SAP/JNK, and down-regulated pro-survival factor AKT in SMS-KCNR cells. Moreover, 7Me-IEITC displayed anti-proliferative effects (IC(50) at 600 nM) and caused an arrest in cell cycle progression. This wide effect of 7Me-IEITC on NB cell signaling and survival suggests that it could be developed as a therapeutic agent against neuroblastoma.
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PMID:Effect of indole ethyl isothiocyanates on proliferation, apoptosis, and MAPK signaling in neuroblastoma cell lines. 1785 93

Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PPIX) is clinically established approach for a number of defined applications. However, in order to optimize the therapeutic benefits of PDT, the specific mode of cell destruction should be better defined. Apoptosis is favored over necrosis for clinical practice as the latter causes more side-effects. In the present study, we analyse PDT-induced cell death and its correlation to various PDT parameters (different doses applied, time after PDT treatment) in vitro using reverse phase protein arrays. Human urothelial cell lines with varying degrees of differentiation (UROtsa, RT4, RT112, J82) were subjected to in vitro-PDT using increasing doses of irradiation. In addition, positive controls for apoptosis, necrosis and un-/specific cellular damage were included. Cells were harvested over a specified time course, lysed and arrayed onto nitrocellulose-covered glass slides. The arrays were analyzed for expression of apoptosis-related proteins by immunohistochemistry. Analysis of caspase-3 and -9 expression, the activation of HIF-1alpha, Bcl2, Cox2 and the phosphorylation of AKT reveals signal activation due to a PDT-stimulus in correlation with the positive controls. Data were analyzed by unsupervised hierarchical clustering and depicted as a heat map revealing cell-specific patterns of pathway stimulation. Higher differentiated phenotypes showed a more distinct signal response in general and a higher apoptotic response in detail. Lower differentiated cell lines lost pathway regulation capabilities according to their state of dedifferentiation. Reverse phase protein arrays are a promising technique for signal pathway profiling: they exceed the range of traditional western blots by sensitivity, high-throughput capability, minimal sample consumption and easy quantification of results obtained.
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PMID:Analyzing effects of photodynamic therapy with 5-aminolevulinic acid (ALA) induced protoporphyrin IX (PPIX) in urothelial cells using reverse phase protein arrays. 1804 85

The role of presenilin-1 (PS1) in neuronal phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in primary neuronal cultures from wild-type (WT) and PS1 null (PS1-/-) embryonic mouse brains. Here we show that in PS1-/- cultures, the onset of neuronal maturation coincides with a decrease in the PI3K-dependent phosphorylation-activation of Akt and phosphorylation-inactivation of glycogen synthase kinase-3 (GSK-3). Mature PS1-/- neurons show increased activation of apoptotic caspase-3 and progressive degeneration preceded by dendritic retraction. Expression of exogenous WT PS1 or constitutively active Akt in PS1-/- neurons stimulates PI3K signaling and suppresses both caspase-3 activity and dendrite retraction. The survival effects of PS1 are sensitive to inhibitors of PI3K kinase but insensitive to gamma-secretase inhibitors. Familial Alzheimer disease (FAD) mutations suppress the ability of PS1 to promote PI3K/AKT signaling, prevent phosphorylation/inactivation of GSK-3 and promote activation of caspase-3. These mutation effects are reversed upon coexpression of constitutively active Akt. Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.
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PMID:Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling. 1818 91

Diphenyl difluoroketone (EF24), a molecule having structural similarity to curcumin, was reported to inhibit proliferation of a variety of cancer cells in vitro. However, the efficacy and in vivo mechanism of action of EF24 in gastrointestinal cancer cells have not been investigated. Here, we assessed the in vivo therapeutic effects of EF24 on colon cancer cells. Using hexosaminidase assay, we determined that EF24 inhibits proliferation of HCT-116 and HT-29 colon and AGS gastric adenocarcinoma cells but not of mouse embryo fibroblasts. Furthermore, the cancer cells showed increased levels of activated caspase-3 and increased Bax to Bcl-2 and Bax to Bcl-xL ratios, suggesting that the cells were undergoing apoptosis. At the same time, cell cycle analysis showed that there was an increased number of cells in the G(2)-M phase. To determine the effects of EF24 in vivo, HCT-116 colon cancer xenografts were established in nude mice and EF24 was given i.p. EF24 significantly suppressed the growth of colon cancer tumor xenografts. Immunostaining for CD31 showed that there was a lower number of microvessels in the EF24-treated animals coupled with decreased cyclooxygenase-2, interleukin-8, and vascular endothelial growth factor mRNA and protein expression. Western blot analyses also showed decreased AKT and extracellular signal-regulated kinase activation in the tumors. Taken together, these data suggest that the novel curcumin-related compound EF24 is a potent antitumor agent that induces caspase-mediated apoptosis during mitosis and has significant therapeutic potential for gastrointestinal cancers.
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PMID:Diphenyl difluoroketone: a curcumin derivative with potent in vivo anticancer activity. 1833 78

We recently identified genes and molecular pathways related to radioresistance of oral squamous cell carcinoma (OSCC) using Affymetrix GeneChip. The current study focused on the association between one of the target genes, intercellular adhesion molecule 2 (ICAM2), and resistance to X-ray irradiation in OSCC cells, and evaluated the antitumor efficacy of combining ICAM2 small interfering RNA (siRNA) and X-ray irradiation. Downregulation of ICAM2 expression by siRNA enhanced radiosensitivity of OSCC cells with the increased apoptotic phenotype via phosphorylation (ser473) of AKT and activation of caspase-3. Moreover, overexpression of ICAM2 induced greater OSCC cell resistance to the X-ray irradiation with the radioresistance phenotype. These results suggested that ICAM2 silencing is closely related to sensitivity of OSCC cells to radiotherapy, and that ICAM2 may be an effective radiotherapeutic target for this disease.
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PMID:Inhibition of ICAM2 induces radiosensitization in oral squamous cell carcinoma cells. 1834 42

Arsenic trioxide (As2O3) is used clinically to treat acute promyelocytic leukemia but is less successful in other malignancies. To identify targets for potential combination therapies, we have begun to characterize signaling pathways leading to As2O3-induced cytotoxicity. Previously, we described the requirement for a reactive oxygen species-mediated, SEK1/c-Jun NH2-terminal kinase (JNK) pathway to induce apoptosis. AKT inhibits several steps in this pathway; therefore, we postulated that As2O3 might decrease its activity. Indeed, As2O3 decreases not only AKT activity but also total AKT protein, and sensitivity to As2O3 correlates with the degree of AKT protein decrease. Decreased AKT expression further correlates with JNK activation and the release of AKT from the JNK-interacting protein 1 scaffold protein known to assemble the mitogen-activated protein kinase cascade. We found that As2O3 regulates AKT protein stability without significant effects on its transcription or translation. We show that As2O3 decreases AKT protein via caspase-mediated degradation, abrogated by caspase-6, caspase-8, caspase-9, and caspase-3 inhibitors but not proteosome inhibitors. Furthermore, As2O3 enhances the ability of a heat shock protein 90 inhibitor to decrease AKT expression and increase growth inhibition. This suggests that As2O3 may be useful in combination therapies that target AKT pathways or in tumors that have constitutively active AKT expression.
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PMID:Arsenic trioxide decreases AKT protein in a caspase-dependent manner. 1856 39

Constitutively activated AKT kinase is a common feature of T-cell acute lymphoblastic leukemia (T-ALL). Here, we report that the novel AKT inhibitor (2S)-1-(1H-indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan2-amine (A443654) leads to rapid cell death of T-ALL lines and patient samples. Treatment of CEM, Jurkat, and MOLT-4 cells with nanomolar doses of the inhibitor led to AKT phosphorylation accompanied by dephosphorylation and activation of the downstream target, glycogen synthase kinase-3beta. Effects were time- and dose-dependent, resulting in apoptotic cell death. Treatment of Jurkat cells with A443654 resulted in activation of caspase-2, -3, -6, -8, and -9. Apoptotic cell death was mostly dependent on caspase-2 activation, as demonstrated by preincubation with a selective pharmacological inhibitor. It is remarkable that A443654 was highly effective against the drug-resistant cell line CEM-VBL100, which expresses 170-kDa P-glycoprotein. Moreover, A443654 synergized with the DNA-damaging agent etoposide in both drug-sensitive and drug-resistant cell lines when coadministered [combination index (CI) = 0.39] or when pretreated with etoposide followed by A443654 (CI = 0.689). The efficacy of A443654 was confirmed using blasts from six patients with T-ALL, all of whom displayed low levels of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and constitutive phosphorylation of Akt on Ser473. At 1 microM, the inhibitor was able to induce apoptotic cell death of T-ALL blast cells, as indicated by flow cytometric analysis of samples immunostained for active (cleaved) caspase-3. Because activated AKT is seen in a large percentage of patients with T-ALL, A443654, either alone or in combination with existing drugs, may be a useful therapy for primary and drug-resistant T-ALL.
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PMID:Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor (2S)-1-(1H-Indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan2-amine (A443654) in T-cell acute lymphoblastic leukemia. 1857 85

Because the phosphatidylinositol-3-kinase-AKT pathway is emerging as an important regulator of tumor cell survival, inhibitors of this pathway have enormous potential in cancer treatment. A specific inhibitor of AKT, [d-3-deoxy-2-O-methyl-myo-inositol-1-[(R)-2-methoxy-3-(octadecyloxy)propyl hydrogen phosphate]] (SH-5) has been recently synthesized, but little is known about its effects on cytokine signaling. We found that SH-5 potentiated the apoptosis induced by tumor necrosis factor (TNF), as indicated by intracellular esterase staining, annexin V staining, and caspase-3 activation. This effect of SH-5 correlated with downregulation of various gene products that mediate cell survival, proliferation, metastasis, and invasion, all known to be regulated by NF-kappaB. SH-5 also blocked NF-kappaB activation induced by TNF-alpha, lipopolysaccharide, phorbol ester, and cigarette smoke but not that activated by hydrogen peroxide and RANK ligand, indicating differential requirement of AKT. Inhibition of NF-kappaB correlated with abrogation of phosphorylation and degradation of IkappaBalpha through the inhibition of activation of IkappaBalpha kinase (IKK). This led to suppression of the phosphorylation and translocation of p65 and also of NF-kappaB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, and IKKbeta but not that induced by p65 transfection. Thus, our results clearly demonstrate that inhibition of AKT leads to potentiation of apoptosis through modulation of NF-kappaB signaling.
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PMID:SH-5, an AKT inhibitor potentiates apoptosis and inhibits invasion through the suppression of anti-apoptotic, proliferative and metastatic gene products regulated by IkappaBalpha kinase activation. 1860 97


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