Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer
Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer
复制标题
水飞蓟宾通过激活宫颈癌中 Drp1 依赖性线粒体裂变诱导 G2/M 细胞周期停滞
DOI：
10.3389/fphar.2020.00271
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发表时间：
2020-03
影响因子：
5.6
通讯作者：
Xiaoshan Zhao
中科院分区：
文献类型：
--
作者：
Yanting You;Qiuxing He;Hanqi Lu;Xinghong Zhou;Liqian Chen;Huaxi Liu;Zibin Lu;Dongyi Liu;Yanyan Liu;Daming Zuo;Xiuqiong Fu;Hiuyee Kwan;Xiaoshan Zhao
宫颈癌是全球女性第四大癌症类型和第二大常见妇科恶性肿瘤。水飞蓟宾(Slibinin，SB)是水飞蓟属植物中一种主要的天然多酚类黄酮类化合物，具有保护肝细胞的作用，已被临床应用。它还通过诱导细胞凋亡和细胞周期停滞而具有抗癌作用。然而，Sb通过线粒体分裂对宫颈癌细胞的影响还没有研究。在这里，我们发现SB通过激活动力蛋白相关蛋白1(Drp1)而诱导G2/M细胞周期停滞，从而显著抑制宫颈细胞的增殖，进而在体外和体内介导线粒体分裂功能障碍。SB可降低宫颈细胞的ATP含量、线粒体膜电位和线粒体DNA拷贝数，降低细胞内的氧自由基水平。此外，Sb还可诱导线粒体过度碎裂，减少小管形成。进一步的研究表明，Drp1基因的敲除通过抑制线粒体分裂途径，取消了SB诱导的宫颈癌细胞G2/M期停滞。更重要的是，SB在体内模型中抑制了Hela细胞的生长。总之，我们首次证明SB通过激活依赖于Drp1的线粒体分裂功能障碍来诱导宫颈癌细胞G2/M细胞周期停滞。本研究提出了诱导依赖于Drp1的线粒体分裂来预防和治疗宫颈癌的策略。
Cervical cancer is the fourth leading cancer type and the second most common gynecological malignancy among women worldwide. Silibinin (SB), a chief bioactive natural polyphenolic flavonoid of Silybum marianum L., has been used clinically for its hepatocyte protective effects. It also has anticancer effects via the induction of apoptosis and cell cycle arrest. However, the effects of SB on cervical cancer cells through mitochondrial fission have not been studied. Here, we showed that SB markedly suppressed cervical cell proliferation by inducing G2/M cell cycle arrest via the activation of dynamin-related protein 1 (Drp1), which in turn mediated the mitochondrial fission dysfunction both in vitro and in vivo. SB decreased the ATP content, mitochondrial membrane potential, and mtDNA copy number, as well as reduced the reactive oxygen species levels in cervical cells. Furthermore, SB induced excessive mitochondrial fragmentation and reduced tubule formation. Further study showed that knockdown of Drp1 abolished the SB-induced G2/M cell cycle arrest in cervical cancer cells by inhibiting the mitochondrial fission pathway. More importantly, SB inhibited Hela cell growth in vivo model. In conclusion, we are the first to demonstrate that SB induces cervical cancer cell G2/M cell cycle arrest by activating Drp1-dependent mitochondrial fission dysfunction. This study suggests the strategy of inducing Drp1-dependent mitochondrial fission for cervical cancer prevention and treatment.
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DOI：
10.1126/science.1219855
发表时间：
2012-08-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Youle RJ;van der Bliek AM
通讯作者：
van der Bliek AM
影响因子：
11.8
作者：
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通讯作者：
Li, Jian Jian
影响因子：
7.2
作者：
Moore, David H.
通讯作者：
Moore, David H.
影响因子：
--
作者：
Liu, Jiamei;Wang, Danbo;Li, Weishan
通讯作者：
Li, Weishan
ROS 介导的 CaMKII 激活和线粒体易位通过异鼠李素和氯喹促进三阴性乳腺癌细胞中 Drp1 依赖性线粒体裂变和凋亡
DOI：
10.1186/s13046-019-1201-4
发表时间：
2019-05-28
影响因子：
11.3
作者：
Hu, Jinjiao;Zhang, Yanhao;Gao, Ning
通讯作者：
Gao, Ning