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

Abstract 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 2 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 2 ‐induced apoptosis by enhancing construction of the death‐inducing signaling complex (DISC). NaAsO 2 ‐sensitized DR5 elevation required maintainable transcription and its transcription factor C/EBP homologous protein (CHOP). Further results showed that NaAsO 2 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 2 ‐induced CHOP and DR5 expressions. In addition, the antioxidant N‐acetyl‐l‐cysteine (NAC) treatment led to amelioration of NaAsO 2 ‐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 2 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.