Pro-apoptotic signaling induced by photo-oxidative ER stress is amplified by Noxa, not Bim

Abstract

Pro-apoptotic signaling instigated by endoplasmic reticulum (ER) stress is tightly governed by the BH3-only proteins like Noxa and Bim, which help trigger apoptosis, in part by inactivating mitochondria protecting proteins like Mcl-1. Bim/Noxa-based pro-apoptotic signaling has been implicated for various ER stressors but not yet for those causing "ER-focused" production of severe oxidative stress. In the present study we found that photo-oxidative (phox)-ER stress induced by hypericin-based photodynamic therapy is associated with activation of PERK (an ER sessile, stress sensor), robust induction of CHOP (a pro-apoptotic transcription factor) and induction of Bim and Noxa (accompanied by an eventual drop in Mcl-1 levels). Interestingly Noxa, but not Bim, contributed toward phox-ER stress induced apoptosis, regulated by PERK in a CHOP-independent, temporally-defined manner. These observations shed further light on complex signaling pathways elicited byphox-ER stress and vouch for directing more investigation toward the role of PERK in cell death governance.

Keywords: Apoptosis; Bim; Bladder cancer; C/EBP homologous protein; CHOP; Cell death; ER; Endoplasmic reticulum stress; GRP78; Hyp-PDT; Hypericin; ICD; MEF; PERK; Photodynamic therapy (PDT); Phox; ROS; UPR; eIF2a; endoplasmic reticulum; eukaryotic initiation factor-2a; glucose regulated protein 78; hypericin-based photodynamic therapy; immunogenic cell death; murine embryonic fibroblast; pancreatic ER kinase (PKR)-like ER kinase; photo-oxidative; reactive oxygen species; unfolded protein response.