Kaempferol induces autophagic cell death of hepatocellular carcinoma cells via activating AMPK signaling.
Kaempferol induces autophagic cell death of hepatocellular carcinoma cells via activating AMPK signaling.
复制标题
DOI：
10.18632/oncotarget.21043
复制
发表时间：
2017-10-17
期刊：
影响因子：
--
通讯作者：
Wang XJ
中科院分区：
文献类型：
--
作者：
Han B;Yu YQ;Yang QL;Shen CY;Wang XJ
在本研究中，我们证明山奈酚抑制已建立的人肝细胞癌（HCC）细胞系（HepG 2，Huh-7，BEL 7402和SMMC）和原代人HCC细胞的存活和增殖。山奈酚处理HCC细胞诱导了AMP活化蛋白激酶（AMPK）的激活，导致Ulk 1磷酸化，mTOR复合物1抑制和细胞自噬。自噬诱导通过Beclin-1/自噬基因5上调和p62降解以及轻链3B（LC 3B）-I至LC 3B-II转化和LC 3B斑点形成来反映。通过AMPKα1 shRNA或显性负突变抑制AMPK，可逆转上述信号变化。AMPK抑制也在很大程度上抑制了山萘酚诱导的HCC细胞毒性。通过3-methylaldenine或Beclin-1 shRNA抑制自噬，也保护HCC细胞免受山奈酚的侵害。山奈酚下调黑色素瘤抗原6，AMPK泛素连接酶，导致AMPKα1稳定和积累。我们的结论是山奈酚通过激活AMPK信号抑制人肝癌细胞。
In the present study, we demonstrate that Kaempferol inhibited survival and proliferation of established human hepatocellular carcinoma (HCC) cell lines (HepG2, Huh-7, BEL7402, and SMMC) and primary human HCC cells. Kaempferol treatment in HCC cells induced profound AMP-activated protein kinase (AMPK) activation, which led to Ulk1 phosphorylation, mTOR complex 1 inhibition and cell autophagy. Autophagy induction was reflected by Beclin-1/autophagy gene 5 upregulation and p62 degradation as well as light chain 3B (LC3B)-I to LC3B-II conversion and LC3B puncta formation. Inhibition of AMPK, via AMPKα1 shRNA or dominant negative mutation, reversed above signaling changes. AMPK inhibition also largely inhibited Kaempferol-induced cytotoxicity in HCC cells. Autophagy inhibition, by 3-methyaldenine or Beclin-1 shRNA, also protected HCC cells from Kaempferol. Kaempferol downregulated melanoma antigen 6, the AMPK ubiquitin ligase, causing AMPKα1 stabilization and accumulation. We conclude that Kaempferol inhibits human HCC cells via activating AMPK signaling.