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      Keap1 inhibition sensitizes head and neck squamous cell carcinoma cells to ionizing radiation via impaired non-homologous end joining and induced autophagy

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          Abstract

          The function of Keap1 (Kelch-like ECH-associated protein 1), a sensor of oxidative and electrophilic stress, in the radiosensitivity of cancer cells remains elusive. Here, we investigated the effects of pharmacological inhibition of Keap1 with ML344 on radiosensitivity, DNA double-strand break (DSB) repair and autophagy in head and neck squamous cell carcinoma (HNSCC) cell lines. Our data demonstrate that Keap1 inhibition enhances HNSCC cell radiosensitivity. Despite elevated, Nrf2-dependent activity of non-homologous end joining (NHEJ)-related DNA repair, Keap1 inhibition seems to impair DSB repair through delayed phosphorylation of DNA-PKcs. Moreover, Keap1 inhibition elicited autophagy and increased p62 levels when combined with X-ray irradiation. Our findings suggest HNSCC cell radiosensitivity, NHEJ-mediated DSB repair, and autophagy to be co-regulated by Keap1.

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            The cBio Cancer Genomics Portal (http://cbioportal.org) is an open-access resource for interactive exploration of multidimensional cancer genomics data sets, currently providing access to data from more than 5,000 tumor samples from 20 cancer studies. The cBio Cancer Genomics Portal significantly lowers the barriers between complex genomic data and cancer researchers who want rapid, intuitive, and high-quality access to molecular profiles and clinical attributes from large-scale cancer genomics projects and empowers researchers to translate these rich data sets into biologic insights and clinical applications. © 2012 AACR.
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              COSMIC: the Catalogue Of Somatic Mutations In Cancer

              Abstract COSMIC, the Catalogue Of Somatic Mutations In Cancer (https://cancer.sanger.ac.uk) is the most detailed and comprehensive resource for exploring the effect of somatic mutations in human cancer. The latest release, COSMIC v86 (August 2018), includes almost 6 million coding mutations across 1.4 million tumour samples, curated from over 26 000 publications. In addition to coding mutations, COSMIC covers all the genetic mechanisms by which somatic mutations promote cancer, including non-coding mutations, gene fusions, copy-number variants and drug-resistance mutations. COSMIC is primarily hand-curated, ensuring quality, accuracy and descriptive data capture. Building on our manual curation processes, we are introducing new initiatives that allow us to prioritize key genes and diseases, and to react more quickly and comprehensively to new findings in the literature. Alongside improvements to the public website and data-download systems, new functionality in COSMIC-3D allows exploration of mutations within three-dimensional protein structures, their protein structural and functional impacts, and implications for druggability. In parallel with COSMIC’s deep and broad variant coverage, the Cancer Gene Census (CGC) describes a curated catalogue of genes driving every form of human cancer. Currently describing 719 genes, the CGC has recently introduced functional descriptions of how each gene drives disease, summarized into the 10 cancer Hallmarks.
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                Author and article information

                Contributors
                Nils.Cordes@OncoRay.de
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                21 October 2020
                21 October 2020
                October 2020
                : 11
                : 10
                : 887
                Affiliations
                [1 ]GRID grid.4488.0, ISNI 0000 0001 2111 7257, OncoRay—National Center for Radiation Research in Oncology, , Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, ; Dresden, Germany
                [2 ]GRID grid.40602.30, ISNI 0000 0001 2158 0612, Helmholtz-Zentrum Dresden—Rossendorf, Institute of Radiooncology—OncoRay, ; Dresden, Germany
                [3 ]GRID grid.4488.0, ISNI 0000 0001 2111 7257, Department of Radiotherapy and Radiation Oncology, , Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, ; Dresden, Germany
                [4 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, German Cancer Consortium (DKTK), Partner Site Dresden, ; Dresden, Germany
                [5 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                Article
                3100
                10.1038/s41419-020-03100-w
                7578798
                33087706
                4cde9c5f-9a27-4a17-a0c1-5c470bcbaae4
                © The Author(s) 2020

                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
                : 14 April 2020
                : 15 September 2020
                : 16 September 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100005972, Deutsche Krebshilfe (German Cancer Aid);
                Award ID: 70112151
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100011264, EC | EC Seventh Framework Programm | FP7 People: Marie-Curie Actions (FP7-PEOPLE - Specific Programme "People" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013));
                Award ID: 642623
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Cell biology
                head and neck cancer,cell death
                Cell biology
                head and neck cancer, cell death

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