title: 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.
authors.affiliation: Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Verfaillie
authors.forename: Alexander
authors.initials: A
authors.lastname: van Vliet
authors.forename: Abhishek D
authors.initials: AD
authors.lastname: Garg
authors.forename: Michael
authors.initials: M
authors.lastname: Dewaele
authors.forename: Noemi
authors.initials: N
authors.lastname: Rubio
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Gupta
authors.forename: Peter
authors.initials: P
authors.lastname: de Witte
authors.forename: Afshin
authors.initials: A
authors.lastname: Samali
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
mesh_terms: D000818:Animals; D000873:Anthracenes; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000502:physiology
chemical_list: D000873:Anthracenes; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D000091342:Endoplasmic Reticulum Chaperone BiP; D008565:Membrane Proteins; D010569:Perylene; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019892:eIF-2 Kinase; C000606775:BCL2L11 protein, human; C000606776:Bcl2l11 protein, mouse; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C408009:Pmaip1 protein, mouse; C004965:hypericin
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