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      Targeting the Wnt/β-catenin signaling pathway in cancer

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          Abstract

          The aberrant Wnt/β-catenin signaling pathway facilitates cancer stem cell renewal, cell proliferation and differentiation, thus exerting crucial roles in tumorigenesis and therapy response. Accumulated investigations highlight the therapeutic potential of agents targeting Wnt/β-catenin signaling in cancer. Wnt ligand/ receptor interface, β-catenin destruction complex and TCF/β-catenin transcription complex are key components of the cascade and have been targeted with interventions in preclinical and clinical evaluations. This scoping review aims at outlining the latest progress on the current approaches and perspectives of Wnt/β-catenin signaling pathway targeted therapy in various cancer types. Better understanding of the updates on the inhibitors, antagonists and activators of Wnt/β-catenin pathway rationalizes innovative strategies for personalized cancer treatment. Further investigations are warranted to confirm precise and secure targeted agents and achieve optimal use with clinical benefits in malignant diseases.

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          Most cited references150

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          Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.

          The WNT signal transduction cascade is a main regulator of development throughout the animal kingdom. Wnts are also key drivers of most types of tissue stem cells in adult mammals. Unsurprisingly, mutated Wnt pathway components are causative to multiple growth-related pathologies and to cancer. Here, we describe the core Wnt/β-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies for Wnt-based therapies.
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            Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.

            The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.
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              Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors.

              The Wnt/beta-catenin pathway is a family of proteins that is implicated in many vital cellular functions such as stem cell regeneration and organogenesis. Several intra-cellular signal transduction pathways are induced by Wnt, notably the Wnt/beta-catenin dependent pathway or canonical pathway and the non-canonical or beta-catenin-independent pathway; the latter includes the Wnt/Ca2+ and Planar Cell Polarity pathway (PCP). Wnt activation occurs at the intestinal crypt floor, and is critical to optimal maintenance of stem cells. Colorectal cancers show evidence of Wnt signaling pathway activation and this is associated with loss of function of the tumor regulator APC. Wnt activation has been observed in breast, lung, and hematopoietic malignancies and contributes to tumor recurrence. The Wnt pathway cross talks with the Notch and Sonic Hedgehog pathways, which has implications for therapeutic interventions in cancers. There are significant challenges in targeting the Wnt pathway, including finding agents that are efficacious without damaging the system of normal somatic stem cell function in cellular repair and tissue homeostasis. Here, we comprehensively review the Wnt pathway and its interactions with the Notch and Sonic Hedgehog pathways. We present the state of the field in effectors and inhibitors of Wnt signaling, including updates on clinical trials in various cancers with inhibitors of Wnt, Notch, and Sonic Hedgehog.
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                Author and article information

                Contributors
                xinw007@126.com , xinw@sdu.edu.cn
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                4 December 2020
                4 December 2020
                2020
                : 13
                : 165
                Affiliations
                [1 ]GRID grid.460018.b, ISNI 0000 0004 1769 9639, Department of Hematology, , Shandong Provincial Hospital Affiliated to Shandong First Medical University, ; Jinan, 250021 Shandong China
                [2 ]Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021 Shandong China
                [3 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, School of medicine, , Shandong University, ; Jinan, 250021 Shandong China
                [4 ]Shandong Provincial Engineering Research Center of Lymphoma, Jinan, 250021 Shandong China
                [5 ]Branch of National Clinical Research Center for Hematologic Diseases, Jinan, 250021 Shandong China
                [6 ]GRID grid.429222.d, ISNI 0000 0004 1798 0228, National Clinical Research Center for Hematologic Diseases, , the First Affiliated Hospital of Soochow University, ; Suzhou, 250021 China
                Article
                990
                10.1186/s13045-020-00990-3
                7716495
                33276800
                b4515847-0686-4fec-8581-aee60dacea21
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 23 September 2020
                : 2 November 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: No.82000195
                Award Recipient :
                Funded by: National Natural Science Foundation
                Award ID: No. 81270598
                Award ID: No. 81473486
                Award ID: No. 81770210
                Award Recipient :
                Funded by: Key Research and Development Program of Shandong Province
                Award ID: No.2018CXGC1213
                Award Recipient :
                Funded by: Technology Development Projects of Shandong Province
                Award ID: No. 2017GSF18189
                Award Recipient :
                Funded by: Taishan Scholars Program of Shandong Province
                Award ID: No.tsqn201909184
                Award Recipient :
                Funded by: Academic promotion programme of Shandong First Medical University
                Award ID: 2020RC007
                Award Recipient :
                Funded by: Shandong Provincial Hospital Youth Talent Plan
                Funded by: Shandong Provincial Hospital Research Incubation Fund
                Categories
                Review
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy
                wnt/β-catenin signaling pathway,cancer,targeted therapy,cancer stem cell

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