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Quercetin inhibits growth of hepatocellular carcinoma by apoptosis induction in part via autophagy stimulation in mice

机译:槲皮素通过小鼠的自噬刺激抑制凋亡诱导抑制肝细胞癌的生长

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摘要

Quercetin (QCT) has been shown to have anticancer activities associated with apoptosis and autophagy induction. However, whether autophagy is functionally responsible for the inhibitory effect of QCT on hepatocellular carcinoma (HCC) remains elusive. This study aims to investigate if QCT inhibits HCC growth via autophagy induction. The in vitro experiments showed that QCT inhibited the growth of human HCC cells in dose- and time-dependent manners and had minimal cytotoxicity to normal hepatocytes. QCT increased both autophagosomes and autolysosomes in HCC cells, as determined by electron microscopy, GFP-RFP-LC3 fluorescence confocal microscopy and Western blot analysis of autophagy-related biomarkers. Functional assays using pathway-specific inhibitors, activators or siRNAs indicated that QCT stimulated autophagy in part via inhibiting the AKT/mTOR pathway and activating the MAPK pathways. Further functional experiments using autophagy inhibitors demonstrated that QCT induced apoptosis of HCC cells in part via stimulating autophagy. The in vivo studies showed that QCT significantly inhibited tumor growth associated with apoptosis induction and autophagy stimulation, and that inhibition of autophagy significantly alleviated the QCT effect on tumor growth inhibition and apoptosis induction. To the best of our knowledge, this is the first in vivo report to demonstrate that QCT inhibits HCC tumor growth and induces apoptosis in part via stimulation of autophagy. Our results provide strong experimental evidence to support that autophagy stimulation may be an important mechanism by which QCT induces cancer cell apoptosis, and pave the way for further clinical investigations by applying QCT or QCT-rich foods for HCC intervention. (C) 2019 Elsevier Inc. All rights reserved.
机译:已显示槲皮素(QCT)具有与细胞凋亡和自噬诱导相关的抗癌活性。然而,无论自噬是否在功能上对QCT对肝细胞癌(HCC)的抑制作用仍然难以捉摸。本研究旨在调查QCT是否抑制通过自噬诱导的HCC生长。体外实验表明,QCT以剂量和时间依赖的方式抑制人HCC细胞的生长,并且对正常肝细胞具有最小的细胞毒性。 QCT在HCC细胞中增加了自噬体和自糖体,如通过电子显微镜,GFP-RFP-LC3荧光共聚焦显微镜和自噬相关生物标志物的蛋白质印迹分析。使用途径特异性抑制剂,活化剂或siRNA的功能测定表明QCT通过抑制AKT / mTOR途径和激活MAPK途径刺激自噬。使用自噬抑制剂的进一步功能实验证明QCT通过刺激自噬部分诱导HCC细胞的凋亡。体内研究表明,QCT显着抑制与凋亡诱导和自噬刺激相关的肿瘤生长,并且对自噬的抑制显着缓解了对肿瘤生长抑制和凋亡诱导的QCT影响。据我们所知,这是第一个在体内报告中证明QCT抑制HCC肿瘤生长并通过刺激自噬诱导细胞凋亡。我们的结果提供了强有力的实验证据,支持自噬刺激可能是QCT诱导癌细胞凋亡的重要机制,并通过应用QCT或QCT的富含HCC干预来铺平进一步的临床研究。 (c)2019 Elsevier Inc.保留所有权利。

著录项

  • 来源
    《The Journal of Nutritional Biochemistry》 |2019年第2019期|共12页
  • 作者单位

    Nanjing Univ Chinese Med Affiliated Hosp 138 Xianlin Ave Nanjing 210023 Jiangsu Peoples R China;

    Nanjing Univ Chinese Med Affiliated Hosp 138 Xianlin Ave Nanjing 210023 Jiangsu Peoples R China;

    Nanjing Univ Chinese Med Coll Basic Med Nanjing Jiangsu Peoples R China;

    Nanjing Univ Chinese Med Affiliated Hosp 138 Xianlin Ave Nanjing 210023 Jiangsu Peoples R China;

    Nanjing Univ Chinese Med Jiangsu Collaborat Innovat Ctr Tradit Chinese Med Clin Med Coll 1 Nanjing Jiangsu Peoples R China;

    Nanjing Univ Chinese Med Affiliated Hosp 138 Xianlin Ave Nanjing 210023 Jiangsu Peoples R China;

    Nanjing Univ Chinese Med Affiliated Hosp 138 Xianlin Ave Nanjing 210023 Jiangsu Peoples R China;

    Harvard Med Sch Beth Israel Deaconess Med Ctr Dept Surg Nutr Metab Lab Boston MA 02115 USA;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

    Quercetin; Hepatocellular carcinoma; Autophagy; Apoptosis; AKT/mTOR; MAPK;

    机译:槲皮素;肝细胞癌;自噬;凋亡;Akt / mtor;MAPK;

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