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A new ER-specific photosensitizer unravels (1)O2-driven protein oxidation and inhibition of deubiquitinases as a generic mechanism for cancer PDT.

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Pinto Fernandez, Adan [UCL] Mace, Yohan [UCL] Drouet, Fleur [UCL] Bony, Emilie [UCL] Boidot, Romain [UCL] Draoui, Nihed [UCL] Lobysheva, Irina [UCL] Corbet, Cyril [UCL] Polet, Florence [UCL] Martherus, Sarkies-Ruben-Matthe [UCL] Deraedt, Quentin [UCL] Schicke, Olivier [UCL] Delvaux, David [UCL] Louis, Caroline [UCL] Dessy, Chantal [UCL] Elias, Benjamin [UCL] Quetin-Leclercq, Joëlle [UCL] Riant, Olivier [UCL] Feron, Olivier [UCL]

Photosensitizers (PS) are ideally devoid of any activity in the absence of photoactivation, and rely on molecular oxygen for the formation of singlet oxygen ((1)O2) to produce cellular damage. Off-targets and tumor hypoxia therefore represent obstacles for the use of PS for cancer photodynamic therapy. Herein, we describe the characterization of OR141, a benzophenazine compound identified through a phenotypic screening for its capacity to be strictly activated by light and to kill a large variety of tumor cells under both normoxia and hypoxia. This new class of PS unraveled an unsuspected common mechanism of action for PS that involves the combined inhibition of the mammalian target of rapamycin (mTOR) signaling pathway and proteasomal deubiquitinases (DUBs) USP14 and UCH37. Oxidation of mTOR and other endoplasmic reticulum (ER)-associated proteins drives the early formation of high molecular weight (MW) complexes of multimeric proteins, the concomitant blockade of DUBs preventing their degradation and precipitating cell death. Furthermore, we validated the antitumor effects of OR141 in vivo and documented its highly selective accumulation in the ER, further increasing the ER stress resulting from (1)O2 generation upon light activation.Oncogene advance online publication, 21 December 2015; doi:10.1038/onc.2015.474.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2016
Language Anglais
Journal information "Oncogene" - Vol. 35, no. 30, p. 3976-3985 (2016)
Peer reviewed yes
Publisher Nature Publishing Group ((United Kingdom) Basingstoke)
issn 0950-9232
e-issn 1476-5594
Publication status Publié
Affiliations UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique
UCL - SSS/IREC - Institut de recherche expérimentale et clinique
UCL - SSS/LDRI - Louvain Drug Research Institute
UCL - SST/IMCN/MOST - Molecules, Solids and Reactivity
Links
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Bibliographic reference Pinto Fernandez, Adan ; Mace, Yohan ; Drouet, Fleur ; Bony, Emilie ; Boidot, Romain ; et. al. A new ER-specific photosensitizer unravels (1)O2-driven protein oxidation and inhibition of deubiquitinases as a generic mechanism for cancer PDT.. In: Oncogene, Vol. 35, no. 30, p. 3976-3985 (2016)
Permanent URL http://hdl.handle.net/2078.1/169302