Jinpeng Zhou1, Yang Jiang1,2, Junshuang Zhao1, Haiying Zhang3, Jinlong Fu1, Peng Luo1, Yanju Ma4, Dan Zou5, Huiling Gao6, Jiangfeng Hu7, Ye Zhang5, Zhitao Jing8. 1. Department of Neurosurgery, the First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China. 2. Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 3. International Education College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China. 4. Department of Oncology, Liaoning Province Tumor Hospital, Shenyang, Liaoning, China. 5. The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, Liaoning, China. 6. College of Life and Health Sciences, Northeastern University, Shenyang, Liaoning, China. 7. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 8. Department of Neurosurgery, the First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China. ztjing@cmu.edu.cn.
Abstract
PURPOSE: The iron-chelating agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several human cancers. However, its effects and mechanism of action in glioma are unknown. METHODS: Human glioma cell line LN229 and patient-derived glioma stem cells GSC-42 were applied for both in vitro and in vivo xenograft nude mouse experiments. The anti-tumor effects of Dp44mT were assessed using MTS, EdU, TUNEL, Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation and immunohistochemical assays. RESULTS: We found that Dp44mT can upregulate the expression of the anti-oncogene N-myc downstream-regulated gene (NDRG)2 by directly binding to and activating the RAR-related orphan receptor (ROR)A. In addition, we found that NDRG2 overexpression suppressed inflammation via activation of interleukin (IL)-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling. CONCLUSIONS: Our data indicate that Dp44mT may serve as an effective drug for the treatment of glioma by targeting RORA and enhancing NDRG2-mediated IL-6/JAK2/STAT3 signaling.
PURPOSE: The iron-chelating agent di-2-pyridylketone4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several humancancers. However, its effects and mechanism of action in glioma are unknown. METHODS:Humanglioma cell line LN229 and patient-derived glioma stem cells GSC-42 were applied for both in vitro and in vivo xenograft nude mouse experiments. The anti-tumor effects of Dp44mT were assessed using MTS, EdU, TUNEL, Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation and immunohistochemical assays. RESULTS: We found that Dp44mT can upregulate the expression of the anti-oncogene N-myc downstream-regulated gene (NDRG)2 by directly binding to and activating the RAR-related orphan receptor (ROR)A. In addition, we found that NDRG2 overexpression suppressed inflammation via activation of interleukin (IL)-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling. CONCLUSIONS: Our data indicate that Dp44mT may serve as an effective drug for the treatment of glioma by targeting RORA and enhancing NDRG2-mediated IL-6/JAK2/STAT3 signaling.
Authors: Yao Lu; Dao Xin; Lulu Guan; Mengli Xu; Yalan Yang; Yu Chen; Yuanyuan Yang; Andrea Wang-Gillam; Li Wang; Shanggang Zong; Feng Wang Journal: Front Oncol Date: 2021-11-22 Impact factor: 6.244
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