Unfolded protein response (UPR) is an adaptive reaction for cells to reduce endoplasmic reticulum (ER) stress.In many types of cancers,such as lung cancer and pancreatic cancer,cancer cells may harness ER stress to facilitate their survival and growth.Prion protein (PrP) is a glycosylated cell surface protein that has been shown to be up-regulated in many cancer cells.Since PrP is a protein prone to misfolding,ER stress can result in under-glycosylated PrP,which in turn may activate ER stress.To assess whether ER stress leads to the production of under-glycosylated PrP and whether underglycosylated PrP may contribute to ER stress thus leading to cancer cell apoptosis,we treated different cancer cells with brefeldin A (BFA),thapsigargin (Thps),and tunicamycin (TM).We found that although BFA,Thps,and TM treatment activated UPR,only ATF4 was consistently activated by these reagents,but not other branches of ER stress.However,the canonical PERK-eIF2α-ATF4 did not account for the observed activation of ATF4 in lung cancer cells.In addition,BFA,but neither Thps nor TM,significantly stimulated the expression of cytosolic PrP.Finally,we found that the levels of PrP contributed to anti-apoptosis activity of BFA-induced cancer cell death.Thus,the pathway of BFA-induced persistent ER stress may be targeted for lung and pancreatic cancer treatment.