EC:2.7.11.26 - FACTA Search

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Query: EC:2.7.11.26 (GSK)
6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunohistochemical expression pattern of beta-catenin has been correlated with beta-catenin gene mutations, clinicopathological features, and disease outcome in 69 stage I and II ovarian carcinomas. beta-Catenin expression was localized in the nuclei, in addition to the cytoplasm and membrane, in 11 tumors (16%): nine endometrioid carcinomas with widespread nuclear expression and two serous carcinomas with focal nuclear expression. The remaining 58 carcinomas (84%) only had membranous beta-catenin expression. All but one of the endometrioid carcinomas with nuclear beta-catenin expression had considerable squamous metaplasia, and five of these cases had large areas of endometrioid tumor of low malignant potential. In addition, beta-catenin nuclear expression was observed in atypical epithelial cells in endometriotic glands adjacent to an endometrioid carcinoma. Sequencing was performed on 25 tumors and corresponding normal tissue: all 13 endometrioid tumors as well as 12 carcinomas of other histological types (four serous, two clear cell, two mucinous, and two mixed). There were oncogenic mutations in the phosphorylation sequence for GSK-3beta in exon 3 of the beta-catenin gene in seven endometrioid carcinomas with beta-catenin nuclear expression. Three mutations affected codon 32 (D32G, D32Y, and D32Y), one affected codon 33 (S33C), two affected codon 37 (S37C and S37F), and one affected codon 41 (T41A). No mutations were observed in the other 18 carcinomas analyzed, comprising two endometrioid and two serous carcinomas with beta-catenin nuclear expression, and 14 carcinomas of different histological types with only membranous expression. In the univariate and multivariate survival analyses, beta-catenin nuclear expression was selected as an indicator of good prognosis, because no patient whose tumor expressed beta-catenin in the nuclei showed relapses or died, in contrast to the 19 relapses and deaths among patients with tumors that only had beta-catenin membranous expression, including three of the four patients with endometrioid carcinomas. Oncogenic beta-catenin mutation is characteristic of a group of endometrioid carcinomas with a good prognosis, most of which originate from previous benign or borderline lesions. Endometrioid carcinomas with exclusively membranous expression of beta-catenin seem to represent a different subgroup of carcinomas that probably have a worse prognosis. In early-stage ovarian cancer, determination of the beta-catenin expression pattern could prove to be a useful marker for selecting low-risk patients.
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PMID:beta-catenin expression pattern in stage I and II ovarian carcinomas : relationship with beta-catenin gene mutations, clinicopathological features, and clinical outcome. 1043 45

Akt negatively regulates apoptotic pathways at a premitochondrial level through phosphorylation and modulation of proteins such as Bad, Forkhead proteins, and GSK-3beta. Akt has also been shown to protect cell death at a post-mitochondrial level, although its downstream targets have not been well documented. Here, we demonstrate that Akt, including AKT1 and AKT2, interacts with and phosphorylates X-linked inhibitor of apoptosis protein (XIAP) at residue serine-87 in vitro and in vivo. Phosphorylation of XIAP by Akt protects XIAP from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of XIAP is also inhibited by Akt. Consistent with this, an XIAP mutant introduced into cells which mimics the Akt-phosphorylated form (i.e. XIAP-S87D) displays reduced ubiquitination and degradation as compared with wild type XIAP. The greater stability of XIAP-S87D in cells translated to increased cell survival after cisplatin treatment. Conversely, a mutant that could not be phosphorylated by Akt (XIAP-S87A) was more rapidly degraded and showed increased cisplatin-induced apoptosis. Furthermore, suppression of XIAP by either siRNA or adenovirus of antisense of XIAP induced programmed cell death and inhibited Akt-stimulated cell survival in ovarian cancer cells. These data identify XIAP as a new downstream target of Akt and a potentially important mediator of the effect of Akt on cell survival.
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PMID:Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). 2782 84

Despite considerable efforts to improve early detection and advances in chemotherapy, metastatic relapses remain a major challenge in the management of ovarian cancer. The endothelin A receptor (ET(A)R)/endothelin-1 (ET-1) axis has been shown to have a significant role in ovarian carcinoma by promoting tumorigenesis. Here we show that the ET-1/ET(A)R autocrine pathway drives epithelial-to-mesenchymal transition (EMT) in ovarian tumor cells by inducing a fibroblastoid and invasive phenotype, down-regulation of E-cadherin, increased levels of beta-catenin, Snail, and other mesenchymal markers, and suppression of E-cadherin promoter activity. Activation of ET(A)R by ET-1 triggers an integrin-linked kinase (ILK)-mediated signaling pathway leading to glycogen synthase kinase-3beta (GSK-3beta) inhibition, Snail and beta-catenin stabilization, and regulation of transcriptional programs that control EMT. Transfection of dominant negative ILK or exposure to an ILK inhibitor suppresses the ET-1-induced phosphorylation of GSK-3beta as well as Snail and beta-catenin protein stability, activity, and invasiveness, indicating that ET-1/ET(A)R-induced EMT-promoting effects depend on ILK. ET(A)R blockade by specific antagonists or reduction by ET(A)R RNA interference reverses EMT and cell invasion by inhibiting autocrine signaling pathways. In ovarian carcinoma xenografts, ABT-627, a specific ET(A)R antagonist, suppresses EMT determinants and tumor growth. In human ovarian cancers, ET(A)R expression is associated with E-cadherin down-regulation, N-cadherin expression, and tumor grade. Collectively, these findings provide evidence of a critical role for the ET-1/ET(A)R axis during distinct steps of ovarian carcinoma progression and identify novel targets of therapeutic intervention.
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PMID:Endothelin-1 promotes epithelial-to-mesenchymal transition in human ovarian cancer cells. 1635 76

The endothelin-1 (ET-1) axis represents a novel target in several malignancies, including ovarian carcinoma. Upon being activated, the endothelin A receptor (ET(A)R) mediates multiple tumor-promoting activities, including mitogenesis, escape from apoptosis, angiogenesis, metastasis-related protease activation, epithelial-mesenchymal transition, and invasion. Integrin-linked kinase (ILK) is a multidomain focal adhesion protein that conveys intracellular signaling elicited by beta1-integrin and growth factor receptors. In this study, we investigate whether the signaling triggered by ET(A)R leading to an aggressive phenotype is mediated by an ILK-dependent mechanism. In HEY and OVCA 433 ovarian carcinoma cell lines, activation of ET(A)R by ET-1 enhances the expression of alpha2beta1 and alpha3beta1 integrins. ILK activity increases as ovarian cancer cells adhere to type I collagen through beta1 integrin signaling, and do so to a greater extent on ET-1 stimulation. ET-1 increases ILK mRNA and protein expression and activity in a time- and concentration-dependent manner. An ILK small-molecule inhibitor (KP-392) or transfection with a dominant-negative ILK mutant effectively blocks the phosphorylation of downstream signals, Akt and glycogen synthase kinase-3beta. The blockade of ET-1/ET(A)R-induced ILK activity results in an inhibition of matrix metalloproteinase activation as well as of cell motility and invasiveness in a phosphoinositide 3 kinase-dependent manner. In ovarian carcinoma xenografts, ABT-627, a specific ET(A)R antagonist, suppresses ILK expression, Akt and glycogen synthase kinase-3beta phosphorylation, and tumor growth. These data show that ILK functions as a downstream mediator of the ET-1/ET(A)R axis to potentiate aggressive cellular behavior. Thus, the ILK-related signaling cascade can be efficiently targeted by pharmacologic blockade of ET(A)R.
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PMID:Integrin-linked kinase functions as a downstream mediator of endothelin-1 to promote invasive behavior in ovarian carcinoma. 1664 53

Although glycogen synthase kinase-3 (GSK-3) might act as a tumor suppressor since its inhibition is expected to mimic the activation of Wnt-signaling pathway, GSK-3beta may contribute to NF-kappaB activation in cancer cells leading to increased cancer cell proliferation and survival. Here we report that GSK-3beta activity was involved in the proliferation of human ovarian cancer cell both in vitro and in vivo. Inhibition of GSK-3 activity by pharmacological inhibitors suppressed proliferation of the ovarian cancer cells. Overexpressing constitutively active form of GSK-3beta induced entry into the S phase, increased cyclin D1 expression and facilitated the proliferation of ovarian cancer cells. Furthermore, GSK-3 inhibition prevented the formation of the tumor in nude mice generated by the inoculation of human ovarian cancer cells. Our findings thus suggest that GSK-3beta activity is important for the proliferation of ovarian cancer cells, implicating this kinase as a potential therapeutic target in ovarian cancer.
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PMID:Glycogen synthase kinase-3beta positively regulates the proliferation of human ovarian cancer cells. 1684 34

In ovarian carcinoma, acquisition of invasiveness is accompanied by the loss of the epithelial features and the gain of a mesenchymal phenotype, a process known as epithelial-mesenchymal transition (EMT). The endothelin A receptor (ET(A)R)/endothelin-1 (ET-1) axis is overexpressed in primary and metastatic ovarian carcinoma. In this tumor type, the ET-1/ET(A)R axis has a critical role in ovarian carcinoma progression by inducing proliferation, survival, neoangiogenesis, loss of intercellular communication and invasion. Recently, we demonstrated that the ET-1/ET(A)R autocrine pathway drives EMT in ovarian tumor cells by inducing an invasive phenotype through downregulation of E-cadherin, increased levels of beta-catenin, Snail and other mesenchymal markers, and suppression of E-cadherin promoter activity. Activation of ET(A)R by ET-1 triggers a phosphatidylinositol 3-kinase-dependent integrin-linked kinase (ILK)-mediated signaling pathway leading to glycogen synthase kinase-3beta (GSK-3beta) inhibition, Snail and beta-catenin stabilization and transcriptional programs that control EMT. Transfection of dominant negative ILK or exposure to an ILK inhibitor suppresses the ET-1-induced phosphorylation of GSK-3beta as well as Snail and beta-catenin protein stability, transcriptional activity and invasiveness, indicating that ET-1/ET(A)R-induced EMT depends on ILK activity. ET(A)R blockade by specific antagonists, or reduction by ET(A)R RNA interference, reverses EMT and cell invasion by inhibiting autocrine signaling pathways. In ovarian carcinoma xenografts, the specific ET(A)R antagonist ABT-627 suppresses EMT determinants and tumor growth. In human ovarian cancers, ET(A)R expression is associated with E-cadherin downregulation, N-cadherin expression and tumor grade. In conclusion, our findings demonstrate that ET(A)R activation by ET-1 is a key mechanism of the complex signaling network that promotes EMT as well as ovarian cancer cell invasion. The small molecule ET(A)R antagonist achieves concomitant suppression of tumor growth and EMT effectors, providing a new opportunity for therapeutic intervention in which targeting ILK pathway and the related Snail and beta-catenin signaling cascade via ET(A)R blockade may be advantageous in the treatment of ovarian cancer.
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PMID:Epithelial-mesenchymal transition in ovarian cancer progression: a crucial role for the endothelin axis. 1758 12

Elevated activin A levels in serum, cyst fluid, and peritoneal fluid of ovarian cancer patients suggest a role for this peptide hormone in disease development. We hypothesize that activin A plays a role in ovarian tumor biology, and analyzed activin-mediated pro-oncogenic signaling in vitro and the expression of activin signaling pathway molecules in vivo. Activin A regulation of Akt and GSK, and the effects of repressing the activities of these molecules (with pharmacological inhibitors) on cellular proliferation were assessed in the cell line, OVCA429. Activin A activated Akt, which phosphorylated GSK, repressing GSK activity in vitro. Activin A stimulated cellular proliferation and repression of GSK augmented activin-regulated proliferation. To validate in vitro observations, immunostaining of the betaA-subunit of activin A and phospho-GSKalpha/beta (Ser9/21) was performed, and the correlation between immunoreactivity levels of these markers and survival was evaluated in benign serous cystadenoma, borderline tumor, and cystadenocarcinoma microarrays. Analysis of tissue microarrays revealed that betaA expression in epithelia did not correlate with survival or malignancy, but expression was elevated in stromal cells from carcinomas when compared with benign tumors. Phospho-GSKalpha/beta (Ser9/21) staining was more intense in mitotically active carcinoma cells and exhibited a polarized localization in benign neoplasms that was absent in carcinomas. Notably, lower phospho-GSKalpha/beta (Ser9/21) immunoreactivity correlated with better survival for carcinoma patients (P=0.046). Our data are consistent with a model in which activin A may mediate ovarian oncogenesis by activating Akt and repressing GSK to stimulate cellular proliferation.
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PMID:The role of activin A and Akt/GSK signaling in ovarian tumor biology. 1845 Sep 71

D- and E-type cyclins mediate G(1)-S phase cell cycle progression through activation of specific cyclin-dependent kinases (cdk) that phosphorylate the retinoblastoma protein (pRb), thereby alleviating repression of E2F-DP transactivation of S-phase genes. Cyclin D1 is often overexpressed in a variety of cancers and is associated with tumorigenesis and metastasis. Loss of cyclin D can cause G(1) arrest in some cells, but in other cellular contexts, the downstream cyclin E protein can substitute for cyclin D and facilitate G(1)-S progression. The objective of this study was to determine if a flexible heteroarotinoid anticancer compound, SHetA2, regulates cell cycle proteins and cell cycle progression in ovarian cancer cells. SHetA2 induced cyclin D1 phosphorylation, ubiquitination, and proteasomal degradation, causing G(1) arrest in ovarian cancer cells despite continued cyclin E2 expression and independently of p53 and glycogen synthase kinase-3beta. Cyclin D1 loss inhibited pRb S780 phosphorylation by cyclin D1-cdk4/6 and released p21 from cyclin D1-cdk4/6-p21 protein complexes to form cyclin E2-cdk2-p21 complexes, which repressed phosphorylation of pRb S612 by cyclin E2-cdk2 and ultimately E2F-DP transcriptional activity. G(1) arrest was prevented by overexpression or preventing degradation of cyclin D1 but not by restoration of pRb S612 phosphorylation through p21 knockdown. In conclusion, we show that loss of cyclin D1 in ovarian cancer cells treated with SHetA2 is sufficient to induce G(1) cell cycle arrest and this strategy is not impeded by the presence of cyclin E2. Therefore, cyclin D1 is a sufficient therapeutic target in ovarian cancer cells.
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PMID:Cyclin D1 degradation is sufficient to induce G1 cell cycle arrest despite constitutive expression of cyclin E2 in ovarian cancer cells. 1963 77

Combination of innocuous dietary components with anticancer drugs is an emerging new strategy for cancer chemotherapy to increase antitumor responses. Tangeretin is a citrus flavonoid known to inhibit cancer cell proliferation. Here, we show an enhanced response of A2780/CP70 and 2008/C13 cisplatin-resistant human ovarian cancer cells to various combination treatments of cisplatin and tangeretin. Pretreatment of cells with tangeretin before cisplatin treatment synergistically inhibited cancer cell proliferation. This combination was effective in activating apoptosis via caspase cascade as well as arresting cell cycle at G(2)-M phase. Moreover, phospho-Akt and its downstream substrates, e.g., NF-kappaB, phospho-GSK-3beta, and phospho-BAD, were downregulated upon tangeretin-cisplatin treatment. The tangeretin-cisplatin-induced apoptosis in A2780/CP70 cells was increased by phosphoinositide-3 kinase (PI3K) inhibition and siRNA-mediated Akt silencing, but reduced by overexpression of constitutively activated Akt and GSK-3beta inhibition. The overall results indicated that tangeretin exposure preconditions cisplatin-resistant human ovarian cancer cells for a conventional response to low-dose cisplatin-induced cell death occurring through downregulation of PI3K/Akt signaling pathway. Thus, effectiveness of tangeretin combinations, as a promising modality in the treatment of resistant cancers, warrants systematic clinical studies.
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PMID:Tangeretin sensitizes cisplatin-resistant human ovarian cancer cells through downregulation of phosphoinositide 3-kinase/Akt signaling pathway. 1990 49

The contribution of the endothelin-1 (ET-1)/ET A receptor (ETAR) axis in tumor growth and progression is investigated in many tumor types, including ovarian carcinoma. In ovarian cancer cells, ET-1 acts as an autocrine growth factor selectively through the ETAR triggering the concomitant activation of multiple pathways. In these cells, the involvement of beta-arrestin-1 as signal transducer in ET-1-dependent signalling pathways has been recently highlighted. Because several G protein-coupled receptors have been shown to activate signalling pathways in a beta-arrestin-dependent manner, in this study we explored whether beta-arrestin-1 is involved in a distinct signalling mechanism linking the ETAR to phosphoinositide 3-kinase (PI3K)/integrin-linked kinase (ILK)/Akt in HEY ovarian cancer cells. The inhibitory effects of ZD4054 (zibotentan), a specific ETAR antagonist, in ET-1-dependent phosphorylation of ILK, Akt, and glycogen synthase kinase (GSK-3beta) demonstrated the involvement of the ETAR in these effects. By using a kinase assay, we demonstrate that beta-arrestin-1 silencing inhibits the ET-1-induced ILK activity in a time-dependent manner and downstream Akt and GSK-3beta phosphorylation. These results reveal that beta-arrestin-1 is implicated as an ETAR-transducer in the activation of ILK and Akt and in the inactivation of GSK-3beta in response to ET-1 and further support the role of beta-arrestin-1 as a multifunctional adaptor facilitating interprotein interactions critically involved in ETAR-mediated signalling that regulate invasive and metastatic behaviour of ovarian cancer.
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PMID:Beta-arrestin-1 mediates the endothelin-1-induced activation of Akt and integrin-linked kinase. 2072 37

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