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      Drug Design, Development and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the design and development of drugs, as well as the clinical outcomes, patient safety, and programs targeted at the effective and safe use of medicines. Sign up for email alerts here.

      88,007 Monthly downloads/views I 4.319 Impact Factor I 6.6 CiteScore I 1.12 Source Normalized Impact per Paper (SNIP) I 0.784 Scimago Journal & Country Rank (SJR)

       

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      Role of glycogen synthase kinase-3β inhibitor AZD1080 in ovarian cancer

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          Abstract

          Background

          Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase that plays an important role in cancer tumorigenesis and progression. We investigated the role of the GSK-3β inhibitor AZD1080 in ovarian cancer cell lines.

          Methods

          A2780 and OVCAR3 ovarian cancer cell lines were exposed to AZD1080, after which cell proliferation, cell cycle, invasion, and migration assays were performed. Phalloidin staining was used to observe lamellipodia formation. Reverse transcription polymerase chain reaction and Western blot were used to assess the respective mRNA and protein expression levels of GSK-3β, CDK2, CDK1, cyclin D1, matrix metalloproteinase-9 (MMP9), and Bcl-xL.

          Results

          AZD1080 exposure suppressed ovarian cancer cell proliferation, invasion, migration, and lamellipodia formation, and induced G 1 arrest, which was concentration dependent. AZD1080 also significantly downregulated GSK-3β, CDK2, CDK1, cyclin D1, MMP9, and Bcl-xL expression at both mRNA and protein levels.

          Conclusion

          Taken together, our results demonstrate that the GSK-3β inhibitor AZD1080 suppresses ovarian cancer development and therefore may indicate a new direction for ovarian cancer treatment.

          Most cited references24

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          The renaissance of GSK3.

          P. Cohen, S Frame (2001)
          Glycogen synthase kinase 3 (GSK3) was initially described as a key enzyme involved in glycogen metabolism, but is now known to regulate a diverse array of cell functions. The study of the substrate specificity and regulation of GSK3 activity has been important in the quest for therapeutic intervention.
          Article 0 comments Cited 354 times – based on 0 reviews     Review now
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            Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation.

            Jeongwu Lee, Yuri Kotliarov, Svetlana Kotliarova … (2008)
            Glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, is involved in diverse cellular processes ranging from nutrient and energy homeostasis to proliferation and apoptosis. Its role in glioblastoma multiforme has yet to be elucidated. We identified GSK3 as a regulator of glioblastoma multiforme cell survival using microarray analysis and small-molecule and genetic inhibitors of GSK3 activity. Various molecular and genetic approaches were then used to dissect out the molecular mechanisms responsible for GSK3 inhibition-induced cytotoxicity. We show that multiple small molecular inhibitors of GSK3 activity and genetic down-regulation of GSK3alpha/beta significantly inhibit glioma cell survival and clonogenicity. The potency of the cytotoxic effects is directly correlated with decreased enzyme activity-activating phosphorylation of GSK3alpha/beta Y276/Y216 and with increased enzyme activity inhibitory phosphorylation of GSK3alpha S21. Inhibition of GSK3 activity results in c-MYC activation, leading to the induction of Bax, Bim, DR4/DR5, and tumor necrosis factor-related apoptosis-inducing ligand expression and subsequent cytotoxicity. Additionally, down-regulation of GSK3 activity results in alteration of intracellular glucose metabolism resulting in dissociation of hexokinase II from the outer mitochondrial membrane with subsequent mitochondrial destabilization. Finally, inhibition of GSK3 activity causes a dramatic decrease in intracellular nuclear factor-kappaB activity. Inhibition of GSK3 activity results in c-MYC-dependent glioma cell death through multiple mechanisms, all of which converge on the apoptotic pathways. GSK3 may therefore be an important therapeutic target for gliomas. Future studies will further define the optimal combinations of GSK3 inhibitors and cytotoxic agents for use in gliomas and other cancers.
            Article 0 comments Cited 92 times – based on 0 reviews     Review now
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              Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation.

              Abbas Shakoori, Andrei V Ougolkov, Zhi Wei Yu … (2005)
              Glycogen synthase kinase 3beta (GSK3beta) reportedly has opposing roles, repressing Wnt/beta-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-kappaB pathway on the other. The present investigation was undertaken to clarify the roles of GSK3beta in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3beta expression and amounts of its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of beta-catenin oncoprotein in the tumor cells. Inhibition of GSK3beta activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3beta activity by chemical inhibitors and its expression by RNA interference targeting GSK3beta induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3beta in tumor cell survival and proliferation other than its predicted role as a tumor suppressor, and warrant proposing this kinase as a potential therapeutic target in colorectal cancer.
              Article 0 comments Cited 91 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (iso-abbrev): Drug Des Devel Ther
                Journal ID (publisher-id): Drug Design, Development and Therapy
                Title: Drug Design, Development and Therapy
                Publisher: Dove Medical Press
                ISSN (Electronic): 1177-8881
                Publication date Collection: 2016
                Publication date (Electronic): 18 March 2016
                Volume: 10
                Pages: 1225-1232
                Affiliations
                Department of Gynecology, The First affiliated Hospital of China Medical University, Shenyang, People’s Republic of China
                Author notes
                Correspondence: Yang Zhao, Department of Gynecology, The First Affiliated Hospital of China Medical University, No 155, North of Nanjing Street, Heping Distrcit, Shenyang 110001, Liaoning Province, People’s Republic of China, Tel/fax +86 24 8328 3516, Email yida.zhaoyang@ 123456163.com
                Article
                Publisher ID: dddt-10-1225
                DOI: 10.2147/DDDT.S102506
                PMC ID: 4807899
                PubMed ID: 27051274
                SO-VID: 56c8f17f-a43f-47fc-9054-5459c6d5810e
                Copyright © © 2016 Chen et al. This work is published and licensed by Dove Medical Press Limited
                License:

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: ovarian cancer,gsk-3β inhibitor,azd1080,tumorigenesis,progression
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: ovarian cancer, gsk-3β inhibitor, azd1080, tumorigenesis, progression

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