Details

Autor(en) / Beteiligte

• Pinto, A
• Mace, Y
• Drouet, F
• Bony, E
• Boidot, R
• Draoui, N
• Lobysheva, I
• Corbet, C
• Polet, F
• Martherus, R
• Deraedt, Q
• Rodríguez, J
• Lamy, C
• Schicke, O
• Delvaux, D
• Louis, C
• Kiss, R
• Kriegsheim, A V
• Dessy, C
• Elias, B
• Quetin-Leclercq, J
• Riant, O
• Feron, O

Titel

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

Ist Teil von

• Oncogene, 2016-07, Vol.35 (30), p.3976-3985

Ort / Verlag

New York: Nature Publishing Group

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Photosensitizers (PS) are ideally devoid of any activity in the absence of photoactivation, and rely on molecular oxygen for the formation of singlet oxygen (1O2) 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 identied 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.