ROS-mediated PERK-eIF2α-ATF4 pathway plays an important role in arsenite-induced L-02 cells apoptosis via regulating CHOP-DR5 signaling.

Chronic exposure to arsenic remains a worldwide environmental health issue, affecting hundreds of millions of people. Although, arsenic-induced oxidative stress and apoptosis have been determined, the underlying apoptosis mechanism has not been fully elucidated yet. Oxidative stress integrated-ER stress plays an important role in Life-and-Death decision of cells. The current study was to investigate whether NaAsO utilizes oxidative stress integrated-ER stress signaling to exert pro-apoptotic activity in L-02 cells. Results showed that death receptor 5 (DR5) was a mediator of NaAsO -induced apoptosis by enhancing construction of the death-inducing signaling complex (DISC). NaAsO -sensitized DR5 elevation required maintainable transcription and its transcription factor C/EBP homologous protein (CHOP). Further results showed that NaAsO increased expression in biomarker of endoplasmic reticulum (ER) stress and activated the protein kinase R-like ER kinase (PERK)-eukaryotic translation initiation 2α (eIF2α)-activating transcription factor 4 (ATF4) pathway. PERK inhibitor and ATF4 siRNA significantly attenuated NaAsO -induced CHOP and DR5 expressions. In addition, the antioxidant N-acetyl-l-cysteine (NAC) treatment led to amelioration of NaAsO -induced production of reactive oxygen species (ROS) and some ER stress- and apoptosis- related protein levels and cell viability. Taken together, the results indicate that ROS-mediated PERK-eIF2α-ATF4 pathway activated by NaAsO is the critical upstream event for subsequent apoptosis induction via regulating CHOP-DR5 signaling in L-02 cells when chronic exposure to arsenic, and support that antioxidants might be potential therapeutic agents for preventing or delaying the onset and progress of arsenic-induced hepatotoxicity.