title: Role of ER stress response in photodynamic therapy: ROS generated in different subcellular compartments trigger diverse cell death pathways.
abstract: We have analyzed the molecular mechanisms of photoinduced cell death using porphyrins with similar structure differing only in the position of the ethylene glycol (EG) chain on the phenyl ring. Meta- and para-positioned EG chains targeted porphyrins to different subcellular compartments. After photoactivation, both types of derivatives induced death of tumor cells via reactive oxygen species (ROS). Para derivatives pTPP(EG)4 and pTPPF(EG)4 primarily accumulated in lysosomes activated the p38 MAP kinase cascade, which in turn induced the mitochondrial apoptotic pathway. In contrast, meta porphyrin derivative mTPP(EG)4 localized in the endoplasmic reticulum (ER) induced dramatic changes in Ca(2+) homeostasis manifested by Ca(2+) rise in the cytoplasm, activation of calpains and stress caspase-12 or caspase-4. ER stress developed into unfolded protein response. Immediately after irradiation the PERK pathway was activated through phosphorylation of PERK, eIF2α and induction of transcription factors ATF4 and CHOP, which regulate stress response genes. PERK knockdown and PERK deficiency protected cells against mTPP(EG)4-mediated apoptosis, confirming the causative role of the PERK pathway.
authors.affiliation: Department of Molecular Virology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Irena
authors.initials: I
authors.lastname: Moserova
authors.forename: Jarmila
authors.initials: J
authors.lastname: Kralova
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D002118:Calcium / Q000378:metabolism; D053143:Caspase 2 / Q000378:metabolism; D053471:Caspases, Initiator / Q000378:metabolism; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000528:radiation effects*; D019855:Ethylene Glycol / Q000737:chemistry; D055785:Gene Knockdown Techniques; D006706:Homeostasis / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D010778:Photochemotherapy; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002118:Calcium; D053143:Caspase 2; D053471:Caspases, Initiator; D019855:Ethylene Glycol; D011166:Porphyrins; D017382:Reactive Oxygen Species; D019892:eIF-2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases; C093516:CASP4 protein, human