Promotion of Proapoptotic Signals by Lysosomal Photodamage: Mechanistic Aspects and Influence of Autophagy.
Prior studies demonstrated that a low level (LD10-15 ) of lysosomal photodamage can sensitize cells to the apoptotic death that results from subsequent mitochondrial photodamage. We have proposed that this process occurs via a calpain-catalyzed cleavage of the autophagy-associated protein ATG5 to form a proapoptotic fragment. In this report, we provide evidence for the postulated ATG5 cleavage and show that the sequential photodynamic therapy (PDT) protocol can also partly overcome the adverse effect of hypoxia on the initiation of apoptosis. While autophagy can offer cytoprotection after mitochondrial photodamage, this does not appear to apply when lysosomes are the target. This may account for the ability of very low PDT doses directed at lysosomes to evoke ATG5 cleavage. The resulting proapoptotic effect overcomes intrinsic cytoprotection from mitochondrial photodamage along with a further stimulation of phototoxicity.
Department of Pharmacology, Wayne State University, Detroit, MI.
David
D
Kessel
Wellman Center for Photomedicine, Harvard Medical School Massachusetts General Hospital, Boston, MA.
Conor L
CL
Evans
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects* / Q000528:radiation effects; D000071187:Autophagy-Related Protein 5 / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D008027:Light; D008247:Lysosomes / Q000528:radiation effects*; D051379:Mice; D017319:Photosensitizing Agents / Q000494:pharmacology; D011166:Porphyrins / Q000494:pharmacology*
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D017319:Photosensitizing Agents; D011166:Porphyrins; C053434:Talaporfin