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      Is Open Access

      NVP-BSK805, an Inhibitor of JAK2 Kinase, Significantly Enhances the Radiosensitivity of Esophageal Squamous Cell Carcinoma in vitro and in vivo

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          Abstract

          Purpose

          Radiotherapy is one major curative treatment modality for esophageal squamous cell carcinoma (ESCC) patients. This study aimed to find out small-molecular kinase inhibitors, which can significantly enhance the radiosensitivity of ESCC in vitro and in vivo.

          Materials and Methods

          Ninety-three kinase inhibitors were tested for their radiosensitizing effect in ESCC cells through high-content screening. The radiosensitizing effect of kinase inhibitors was investigated in vitro by detection of DNA double-strand breaks (DSBs) and clonogenic survival assay. By the establishment of xenograft tumor models in BALB/c nude mice, the radiosensitizing effect of kinase inhibitors was investigated in vivo.

          Results

          Among the 93 kinase inhibitors tested, we found NVP-BSK805, an inhibitor of JAK2 kinase, significantly radiosensitized ESCC cells through enhancing DSBs, inhibiting DNA damage repair and arresting cell cycle in G2/M or G0/G1 phase. After treatment with NVP-BSK805, ESCC cells showed decreased clonogenic survival and delayed tumor growth in vivo. JAK2 kinase was highly expressed in tumor tissues of ESCC patients, while rarely expressed in matched normal esophageal epithelial tissues. Survival analysis revealed JAK2 kinase as a prognostic factor of ESCC patients treated with chemoradiotherapy.

          Conclusion

          Our study discovered JAK2 kinase as an attractive target to enhance the radiosensitivity of ESCC cells in vitro and in vivo.

          Most cited references23

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          ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1

          Epithelial-mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response (DDR). Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of ATM and upregulation of ZEB1, and ZEB1 promotes tumor cell radioresistance in vitro and in vivo. Mechanistically, ATM kinase phosphorylates and stabilizes ZEB1 in response to DNA damage, and ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitinate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and as the mechanism underlying the association between EMT and radioresistance.
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            Ionizing radiation-induced DNA damage, response, and repair.

            Ionizing radiation (IR) is an effective and commonly employed treatment in the management of more than half of human malignancies. Because IR's ability to control tumors mainly relies on DNA damage, the cell's DNA damage response and repair (DRR) processes may hold the key to determining tumor responses. IR-induced DNA damage activates a number of DRR signaling cascades that control cell cycle arrest, DNA repair, and the cell's fate. DNA double-strand breaks (DSBs) generated by IR are the most lethal form of damage, and are mainly repaired via either homologous recombination (HR) or nonhomologous end-joining (NHEJ) pathways.
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              WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis.

              Idiopathic pulmonary fibrosis (IPF) is characterized by distorted lung architecture and loss of respiratory function. Enhanced (myo)fibroblast activation, ECM deposition, and alveolar epithelial type II (ATII) cell dysfunction contribute to IPF pathogenesis. However, the molecular pathways linking ATII cell dysfunction with the development of fibrosis are poorly understood. Here, we demonstrate, in a mouse model of pulmonary fibrosis, increased proliferation and altered expression of components of the WNT/beta-catenin signaling pathway in ATII cells. Further analysis revealed that expression of WNT1-inducible signaling protein-1 (WISP1), which is encoded by a WNT target gene, was increased in ATII cells in both a mouse model of pulmonary fibrosis and patients with IPF. Treatment of mouse primary ATII cells with recombinant WISP1 led to increased proliferation and epithelial-mesenchymal transition (EMT), while treatment of mouse and human lung fibroblasts with recombinant WISP1 enhanced deposition of ECM components. In the mouse model of pulmonary fibrosis, neutralizing mAbs specific for WISP1 reduced the expression of genes characteristic of fibrosis and reversed the expression of genes associated with EMT. More importantly, these changes in gene expression were associated with marked attenuation of lung fibrosis, including decreased collagen deposition and improved lung function and survival. Our study thus identifies WISP1 as a key regulator of ATII cell hyperplasia and plasticity as well as a potential therapeutic target for attenuation of pulmonary fibrosis.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                24 February 2020
                2020
                : 14
                : 745-755
                Affiliations
                [1 ]Department of Pharmacy, Hangzhou Cancer Hospital , Hangzhou 310002, People’s Republic of China
                [2 ]Hangzhou Cancer Institution, Hangzhou Cancer Hospital , Hangzhou 310002, People’s Republic of China
                [3 ]National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Shenzhen 518116, People’s Republic of China
                Author notes
                Correspondence: Shixiu Wu National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 113 Baohe Street Longgang District, Shenzhen, People’s Republic of China Email wushixiu@medmail.com.cn
                Article
                203048
                10.2147/DDDT.S203048
                7047839
                f39329cf-0043-4637-85e0-37c99fbdeb68
                © 2020 Hua et al.

                This work is published and licensed by Dove Medical Press Limited. 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 27 January 2019
                : 10 January 2020
                Page count
                Figures: 5, References: 26, Pages: 11
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                escc,radioresistance,jak2,nvp-bsk805,dna damage repair
                Pharmacology & Pharmaceutical medicine
                escc, radioresistance, jak2, nvp-bsk805, dna damage repair

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