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Promotion of Proapoptotic Signals by Lysosomal Photodamage
Author(s) -
Kessel David,
Reiners John J.
Publication year - 2015
Publication title -
photochemistry and photobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.818
H-Index - 131
eISSN - 1751-1097
pISSN - 0031-8655
DOI - 10.1111/php.12456
Subject(s) - autophagy , lysosome , programmed cell death , microbiology and biotechnology , mitochondrion , chemistry , apoptosis , cysteine protease , proteases , biology , biochemistry , enzyme
We previously reported that low‐level lysosomal photodamage enhanced the efficacy of subsequent mitochondrial photodamage, resulting in a substantial promotion of apoptotic cell death. We now extend our analysis of the sequential PDT protocol to include two additional lysosomal‐targeting photosensitizers. These agents, because of enhanced permeability, are more potent than the agent (N‐aspartyl chlorin E6, NP e6) used in the initial study. Addition of the cell‐permeable cysteine protease inhibitor E‐64d and calcium chelator BAPTA ‐ AM almost completely suppressed sequential PDT ‐induced loss of mitochondrial membrane potential and activation of procaspases‐3 and ‐7. These inhibitors did not, however, suppress the proapoptotic effect of a BH 3 mimetic or mitochondrial photodamage. Knockdowns of ATG 7 or ATG 5, proteins normally associated with autophagy, suppressed photodamage induced by the sequential PDT protocol. These effects appear to be independent of the autophagic process as pharmacological inhibition of autophagy offered no such protection. Effects of ATG 7 and ATG 5 knockdowns may reflect the role that ATG 7 plays in regulating lysosome permeability, and the likelihood that a proteolytic fragment of ATG 5 amplifies mitochondrial proapoptotic processes. Our results suggest that low‐dose photodamage that sequentially targets lysosomes and mitochondria may offer significant advantages over the use of single photosensitizers.