TTF1‑NP Induces Protective Autophagy During Apoptosis by Inhibiting the Akt/mTOR Pathway and Activating JNK in Human Liver Cancer Cells

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.