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 Ca2+ homeostasis manifested by Ca2+ 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.
Highlights
Photodynamic therapy (PDT) of cancer is based on tumorspecific accumulation of a photosensitizer, followed by irradiation with visible light, resulting in cell death and tumor ablation [1]
Our previous study revealed an important role of p38 MAP kinases (MAPK) signaling in the cell death induced by fluorinated derivative PORF-TEG [23], designated in the current study as pTPPF(EG)4
The step was to examine whether MAPK activation is required for the apoptotic process mediated by mTPP(EG)4 and pTPP(EG)4 as well
Summary
Photodynamic therapy (PDT) of cancer is based on tumorspecific accumulation of a photosensitizer, followed by irradiation with visible light, resulting in cell death and tumor ablation [1]. ROS formed upon irradiation, namely singlet oxygen, have a limited lifetime and ability to migrate from the site(s) of their formation. They interact with biologic substrates in the sites of photosensitizer localization. The molecular nature of the photo-oxidized targets has profound influence on the signaling pathways and mode of cell death initiated by PDT. It must be mentioned that PDT-mediated apoptotic/ necrotic outcomes are influenced by the cell type, identity and concentration of the photosensitizer, and light doses used in the PDT protocol. The type of cell death switches from apoptosis to necrosis with the increasing intensity of the insult
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