Photodynamic therapy with redaporfin targets the endoplasmic reticulum and Golgi apparatus |
| |
| Authors: | Lígia C Gomes‐da‐Silva Liwei Zhao Lucillia Bezu Heng Zhou Allan Sauvat Peng Liu Sylvère Durand Marion Leduc Sylvie Souquere Friedemann Loos Laura Mondragón Baldur Sveinbjørnsson Øystein Rekdal Gaelle Boncompain Franck Perez Luis G Arnaut Oliver Kepp Guido Kroemer |
| |
| Affiliation: | 1. Chemistry Department, University of Coimbra, Coimbra, Portugal;2. Faculty of Medicine, University of Paris Sud, Kremlin‐Bicêtre, France;3. Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France;4. Institut National de la Santé et de la Recherche Médicale UMR1138, Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France;5. Gustave Roussy Comprehensive Cancer Center, Villejuif, France;6. CNRS, UMR9196, Villejuif, France;7. Lytix Biopharma AS, Oslo, Norway;8. Institute of Medical Biology, University of Troms?, Troms?, Norway;9. Department of Subcellular Structure and Cellular Dynamics, CNRS, Institut Curie, PSL Research University, Paris, France;10. Sorbonne Paris Cité, Université Paris Descartes, Paris, France;11. Université Pierre et Marie Curie, Paris, France;12. P?le de Biologie, H?pital Européen Georges Pompidou, APsupp‐HP, Paris, France;13. Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden |
| |
| Abstract: | Preclinical evidence depicts the capacity of redaporfin (Redp) to act as potent photosensitizer, causing direct antineoplastic effects as well as indirect immune‐dependent destruction of malignant lesions. Here, we investigated the mechanisms through which photodynamic therapy (PDT) with redaporfin kills cancer cells. Subcellular localization and fractionation studies based on the physicochemical properties of redaporfin revealed its selective tropism for the endoplasmic reticulum (ER) and the Golgi apparatus (GA). When activated, redaporfin caused rapid reactive oxygen species‐dependent perturbation of ER/GA compartments, coupled to ER stress and an inhibition of the GA‐dependent secretory pathway. This led to a general inhibition of protein secretion by PDT‐treated cancer cells. The ER/GA play a role upstream of mitochondria in the lethal signaling pathway triggered by redaporfin‐based PDT. Pharmacological perturbation of GA function or homeostasis reduces mitochondrial permeabilization. In contrast, removal of the pro‐apoptotic multidomain proteins BAX and BAK or pretreatment with protease inhibitors reduced cell killing, yet left the GA perturbation unaffected. Altogether, these results point to the capacity of redaporfin to kill tumor cells via destroying ER/GA function. |
| |
| Keywords: | Golgi apparatus Golgi‐targeting agents photodynamic therapy redaporfin retrograde transport |
|
|
