Quercetin inhibits growth of hepatocellular carcinoma by apoptosis induction in part via autophagy stimulation in mice.
Quercetin inhibits growth of hepatocellular carcinoma by apoptosis induction in part via autophagy stimulation in mice.
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槲皮素部分通过刺激小鼠自噬诱导细胞凋亡来抑制肝细胞癌的生长
DOI：
10.1016/j.jnutbio.2019.03.018
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发表时间：
2019-07
影响因子：
5.6
通讯作者：
Jin-Rong Zhou
中科院分区：
文献类型：
--
作者：
Yi Ji;Li Li;Yan-Xia Ma;Wen-Ting Li;Liu Li;Heng-Zhou Zhu;Mian-Hua Wu;Jin-Rong Zhou
槲皮素（QCT）已被证明具有与细胞凋亡和自噬诱导相关的抗癌活性。然而，自噬是否在功能上负责QCT对肝细胞癌（HCC）的抑制作用仍然难以捉摸。本研究旨在研究QCT是否通过自噬诱导抑制HCC生长。体外实验表明，QCT以剂量和时间依赖性方式抑制人肝癌细胞的生长，对正常肝细胞的细胞毒性极小。通过电子显微镜、GFP-RFP-LC 3荧光共聚焦显微镜和自噬相关生物标志物的Western印迹分析确定，QCT增加了HCC细胞中的自噬体和自溶酶体。使用通路特异性抑制剂、激活剂或siRNA的功能测定表明，QCT部分地通过抑制AKT/mTOR通路和激活MAPK通路来刺激自噬。使用自噬抑制剂的进一步功能实验表明，QCT部分通过刺激自噬诱导HCC细胞凋亡。体内研究表明，QCT显著抑制与凋亡诱导和自噬刺激相关的肿瘤生长，并且抑制自噬显著减轻QCT对肿瘤生长抑制和凋亡诱导的作用。据我们所知，这是第一个在体内报告，证明QCT抑制肝癌肿瘤生长，并诱导细胞凋亡的一部分，通过刺激自噬。我们的研究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，并为进一步应用QCT或富含QCT的食物干预HCC的临床研究铺平了道路。
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.