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      Characterization of a small-molecule inhibitor targeting NEMO/IKKβ to suppress colorectal cancer growth

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          Abstract

          NEMO/IKKβ complex is a central regulator of NF-κB signaling pathway, its dissociation has been considered to be an attractive therapeutic target. Herein, using a combined strategy of molecular pharmacological phenotyping, proteomics and bioinformatics analysis, Shikonin (SHK) is identified as a potential inhibitor of the IKKβ/NEMO complex. It destabilizes IKKβ/NEMO complex with IC 50 of 174 nM, thereby significantly impairing the proliferation of colorectal cancer cells by suppressing the NF-κB pathway in vitro and in vivo. In addition, we also elucidated the potential target sites of SHK in the NEMO/IKKβ complex. Our study provides some new insights for the development of potent small-molecule PPI inhibitors.

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          Most cited references60

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          Hallmarks of Cancer: The Next Generation

          Douglas Hanahan, Robert A. Weinberg (2011)
          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
          Article 0 comments Cited 12374 times – based on 0 reviews     Review now
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            The nuclear factor NF-kappaB pathway in inflammation.

            Toby Lawrence (2009)
            The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. In this article, we describe how genetic evidence in mice has revealed complex roles for the NF-kappaB in inflammation that suggest both pro- and anti-inflammatory roles for this pathway. NF-kappaB has long been considered the "holy grail" as a target for new anti-inflammatory drugs; however, these recent studies suggest this pathway may prove a difficult target in the treatment of chronic disease. In this article, we discuss the role of NF-kappaB in inflammation in light of these recent studies.
            Article 0 comments Cited 999 times – based on 0 reviews     Review now
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              NF-κB, inflammation, immunity and cancer: coming of age

              Koji Taniguchi, Michael Karin (2018)
              Fourteen years have passed since nuclear factor-κB (NF-κB) was first shown to serve as a molecular lynchpin that links persistent infections and chronic inflammation to increased cancer risk. The young field of inflammation and cancer has now come of age, and inflammation has been recognized by the broad cancer research community as a hallmark and cause of cancer. Here, we discuss how the initial discovery of a role for NF-κB in linking inflammation and cancer led to an improved understanding of tumour-elicited inflammation and its effects on anticancer immunity.
              Article 0 comments Cited 871 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Mingliang Ye: mingliang@dicp.ac.cn
                De-an Guo: daguo@simm.ac.cn
                Xiaochi Ma: maxc1978@163.com
                Journal
                Journal ID (nlm-ta): Signal Transduct Target Ther
                Journal ID (iso-abbrev): Signal Transduct Target Ther
                Title: Signal Transduction and Targeted Therapy
                Publisher: Nature Publishing Group UK (London )
                ISSN (Print): 2095-9907
                ISSN (Electronic): 2059-3635
                Publication date (Electronic): 9 March 2022
                Publication date PMC-release: 9 March 2022
                Publication date Collection: 2022
                Volume: 7
                Electronic Location Identifier: 71
                Affiliations
                [1 ]GRID grid.411971.b, ISNI 0000 0000 9558 1426, Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, ; Dalian, 116000 China
                [2 ]GRID grid.411971.b, ISNI 0000 0000 9558 1426, College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, ; Dalian, 116044 China
                [3 ]GRID grid.417303.2, ISNI 0000 0000 9927 0537, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, ; Xuzhou, 221004 China
                [4 ]GRID grid.423905.9, ISNI 0000 0004 1793 300X, CAS Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, ; Dalian, 116023 China
                [5 ]GRID grid.419093.6, ISNI 0000 0004 0619 8396, Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Research Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, ; Shanghai, 201203 China
                [6 ]GRID grid.412540.6, ISNI 0000 0001 2372 7462, Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, ; 1200 Cailun Road, Shanghai, 201203 China
                [7 ]GRID grid.440706.1, ISNI 0000 0001 0175 8217, Neurology Department, , Dalian University Affiliated Xinhua Hospital, ; Dalian, 116021 China
                Author information
                http://orcid.org/0000-0001-6723-0490
                http://orcid.org/0000-0002-2168-2296
                Article
                Publisher ID: 888
                DOI: 10.1038/s41392-022-00888-1
                PMC ID: 8904520
                PubMed ID: 35260565
                SO-VID: 1a6e8252-38ab-4a7c-ac21-e1c9db120c7f
                Copyright © © The Author(s) 2022
                License:

                Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 5 July 2021
                Date revision received : 31 December 2021
                Date accepted : 3 January 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81930112
                Award ID: 82004089
                Award Recipient :
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2022

                Keywords: drug development,target identification
                Data availability:
                Keywords: drug development, target identification

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