Role of ER Stress Response in Photodynamic Therapy: ROS Generated in Different Subcellular Compartments Trigger Diverse Cell Death Pathways

摘要: We have analyzed the molecular mechanisms of photoinduced cell death using porphyrins with similar structure differing only in position ethylene glycol (EG) chain on phenyl ring. Meta- and para-positioned EG chains targeted to different subcellular compartments. After photoactivation, both types derivatives induced tumor cells via reactive oxygen species (ROS). Para pTPP(EG)4 pTPPF(EG)4 primarily accumulated lysosomes activated p38 MAP kinase cascade, which turn mitochondrial apoptotic pathway. In contrast, meta porphyrin derivative mTPP(EG)4 localized endoplasmic reticulum (ER) dramatic changes Ca2+ homeostasis manifested by rise cytoplasm, activation calpains stress caspase-12 or caspase-4. ER developed into unfolded protein response. Immediately after irradiation PERK pathway was through phosphorylation PERK, eIF2α induction transcription factors ATF4 CHOP, regulate response genes. knockdown deficiency protected against mTPP(EG)4-mediated apoptosis, confirming causative role