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      Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma

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          Abstract

          Background:

          Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3 β positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF- κB)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3 β and to assess the anti-cancer effect of GSK-3 β inhibition in RCC.

          Methods:

          Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3 β in human RCCs. We used small molecule inhibitor, RNA interference, western blotting, quantitative RT–PCR, BrDU incorporation and MTS assays to study the effect of GSK-3 β inactivation on renal cancer cell proliferation and survival.

          Results:

          We detected aberrant nuclear accumulation of GSK-3 β in RCC cell lines and in 68 out of 74 (91.89%) human RCCs. We found that pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of renal cancer cells. We observed that inhibition of GSK-3 results in decreased expression of NF- κB target genes Bcl-2 and XIAP and a subsequent increase in renal cancer cell apoptosis. Moreover, we show that GSK-3 inhibitor and Docetaxel synergistically suppress proliferation and survival of renal cancer cells.

          Conclusions:

          Our results show nuclear accumulation of GSK-3 β as a new marker of human RCC, identify that GSK-3 positively regulates RCC cell survival and proliferation and suggest inhibition of GSK-3 as a new promising approach in the treatment of human renal cancer.

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          Most cited references31

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          The glamour and gloom of glycogen synthase kinase-3.

          Glycogen synthase kinase-3 (GSK3) is now recognized as a key component of a surprisingly large number of cellular processes and diseases. Several mechanisms play a part in controlling the actions of GSK3, including phosphorylation, protein complex formation, and subcellular distribution. These are used to control and direct the far-reaching influences of GSK3 on cellular structure, growth, motility and apoptosis. Dysregulation of GSK3 is linked to several prevalent pathological conditions, such as diabetes and/or insulin resistance, and Alzheimer's disease. Therefore, much effort is currently directed towards understanding the functions and control of GSK3, and identifying methods capable of diminishing the deleterious impact of GSK3 in pathological conditions.
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            Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells.

            Recent studies using glycogen synthase kinase-3beta (GSK-3beta)-deficient mouse embryonic fibroblasts suggest that GSK-3beta positively regulates nuclear factor kappaB (NFkappaB)-mediated gene transcription. Because NFkappaB is suggested to participate in cell proliferation and survival pathways in pancreatic cancer, we investigated the role of GSK-3beta in regulating these cellular processes. Herein, we show that pancreatic cancer cells contain a pool of active GSK-3beta and that pharmacologic inhibition of GSK-3 kinase activity using small molecule inhibitors or genetic depletion of GSK-3beta by RNA interference leads to decreased cancer cell proliferation and survival. Mechanistically, we show that GSK-3beta influences NFkappaB-mediated gene transcription at a point distal to the Ikappa kinase complex, as only ectopic expression of the NFkappaB subunits p65/p50, but not an Ikappa kinase beta constitutively active mutant, could rescue the decreased cellular proliferation and survival associated with GSK-3beta inhibition. Taken together, our results simultaneously identify a previously unrecognized role for GSK-3beta in cancer cell survival and proliferation and suggest GSK-3beta as a potential therapeutic target in the treatment of pancreatic cancer.
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              Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418.

              Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 +/- 27 nM), in an ATP-competitive manner (Ki = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 microM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3beta protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by beta-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                17 November 2009
                08 December 2009
                15 December 2009
                : 101
                : 12
                : 2005-2014
                Affiliations
                [1 ]Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2 Yamagata 990-9585, Japan
                [2 ]Department of Pathology, Feinberg School of Medicine, Northwestern University, Ward Building 3-140, 303 E. Chicago Avenue Chicago, IL 60611, USA
                [3 ]Department of Urology, Keio University School of Medicine, Shinano-machi 35, Shinjuku-ku Tokyo, Japan
                [4 ]Division of Oncology Research, Mayo Clinic College of Medicine, 200 First Street Southwest Rochester, MN 55905, USA
                [5 ]Department of Human Pathology (Second Department of Pathology), Yamagata University School of Medicine, Iida-nishi 2-2-2 Yamagata 990-9585, Japan
                Author notes
                [* ]Author for correspondence: ytomita@ 123456med.id.yamagata-u.ac.jp
                Article
                6605437
                10.1038/sj.bjc.6605437
                2795437
                19920820
                ecfa1bd6-a4e7-4cbd-98de-ae43202fa803
                Copyright 2009, Cancer Research UK
                History
                : 05 August 2009
                : 14 October 2009
                : 19 October 2009
                Categories
                Translational Therapeutics

                Oncology & Radiotherapy
                renal cell carcinoma,apoptosis,glycogen synthase kinase-3β
                Oncology & Radiotherapy
                renal cell carcinoma, apoptosis, glycogen synthase kinase-3β

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