Titanium dioxide nanoparticles induce endoplasmic reticulum stress-mediated apoptotic cell death in liver cancer cells

OBJECTIVE: Titanium oxide (TiO(2)) acts as a photosensitizer in photodynamic therapy by mediating reactive oxygen species (ROS)-induced endoplasmic reticulum (ER) stress. This study aimed to investigate the effect of TiO(2) on ER stress in liver cancer cells. METHODS: Normal human liver and human hepatocarcinoma cell lines were incubated with various concentrations of TiO(2) nanotubes for 48 hours. Cell growth, apoptosis, cell cycle, and cellular ROS were detected. Expression levels of ER stress sensors (PERK and ATF6) and Bax were evaluated by western blot. The effect of TiO(2) on liver cancer growth was also investigated in mice in vivo. RESULTS: TiO(2) inhibited cell growth, increased apoptosis and cellular ROS levels, and arrested the cell cycle in G1 stage in liver cancer cells. TiO(2) also increased PERK, ATF6, and Bax expression levels in liver cancer cells in dose-dependent manners. TiO(2) had no significant effect on cell growth, apoptosis, ROS level, cell cycle distribution, or PERK, ATF6, or Bax expression in normal liver cells. TiO(2) administration reduced tumor volume and increased PERK, Bax, and ATF6 expression levels in tumor tissues in vivo. CONCLUSIONS: TiO(2) nanoparticles increased ROS-induced ER stress and activated the PERK/ATF6/Bax axis in liver cancer cells in vitro and in vivo.