TTF1‑NP induces protective autophagy during apoptosis by inhibiting the Akt/mTOR pathway and activating JNK in human liver cancer cells.
TTF1‑NP induces protective autophagy during apoptosis by inhibiting the Akt/mTOR pathway and activating JNK in human liver cancer cells.
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DOI：
10.3892/or.2018.6196
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发表时间：
2018-03
期刊：
影响因子：
4.2
通讯作者：
Xuan Zhang;Meilan Zhang;B. Xiao;Wenjun Jiao;Silin Zhang;Xue-wu Zhang
中科院分区：
文献类型：
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作者：
Xuan Zhang;Meilan Zhang;B. Xiao;Wenjun Jiao;Silin Zhang;Xue-wu Zhang
TTF 1-NP是一种基于5，2 '，4'-三羟基-6，7，5 '-三甲氧基黄酮（TTF 1）的黄酮纳米颗粒，TTF 1来源于长白山药用植物珍珠梅。我们先前证明了TTF 1-NP在人肝癌中的抗肿瘤作用，包括诱导细胞凋亡和抑制血管生成、迁移和侵袭。在此，我们研究了TTF 1-NP对自噬的影响及其与凋亡的关系，并探讨了人类肝癌细胞系中潜在的潜在机制。我们进行了细胞活力测定、膜联蛋白V/碘化丙啶双重染色、Hoechst染色、单丹酰尸胺染色、透射电子显微镜、绿色荧光蛋白轻链3质粒转染和蛋白质印迹。我们发现TTF 1-NP诱导HepG 2和SMMC-7721细胞凋亡和自噬。自噬抑制剂3-甲基腺嘌呤预处理促进TTF 1-NP诱导的细胞凋亡。TTF 1-NP降低了两种细胞系中磷酸化（p）-Akt、p-mTOR和p-ERK 1/2的水平，并增加了p-JNK的水平。用胰岛素、SP 600125和U 0126处理细胞表明Akt/mTOR通路和JNK参与TTF 1-NP-诱导的自噬。总之，这些发现表明TTF 1-NP通过调节HepG 2和SMMC-7721细胞中的Akt/mTOR和JNK通路诱导保护性凋亡相关的自噬。因此，自噬可能是TTF 1-NP治疗人类肝癌的潜在靶点。
TTF1‑NP is a flavonoid nanoparticle based on 5,2',4'‑trihydroxy‑6,7,5'‑trimethoxyflavone (TTF1), which is derived from the medicinal plant Sorbaria sorbifolia that grows in the Changbai Mountain. We previously demonstrated antitumor effects of TTF1‑NP in human hepatoma including induction of apoptosis and inhibition of angiogenesis, migration and invasion. Herein, we examined the effects of TTF1‑NP on autophagy and its relationship with apoptosis, and explored potential underlying mechanisms in human hepatoma cell lines. We conducted cell viability assays, Annexin V/propidium iodide double staining, Hoechst staining, monodansylcadaverine staining, transmission electron microscopy, green fluorescent protein‑light chain 3 plasmid transfection and western blots. We found that TTF1‑NP induced apoptosis and autophagy in HepG2 and SMMC‑7721 cells. Pretreatment with the autophagy inhibitor 3‑methyladenine promoted TTF1‑NP‑induced apoptosis. TTF1‑NP decreased levels of phosphorylated (p)‑Akt, p‑mTOR and p‑ERK1/2 and increased p‑JNK levels in the two cell lines. Treating cells with insulin, SP600125 and U0126 indicated that the Akt/mTOR pathway and JNK were involved in TTF1‑NP‑induced autophagy. Together, these findings suggest that TTF1‑NP induced protective apoptosis‑related autophagy by modulating the Akt/mTOR and JNK pathways in HepG2 and SMMC‑7721 cells. Therefore, autophagy may be a potential target for TTF1‑NP in human hepatoma therapy.