title: New apoptosis cascade mediated by lysosomal enzyme and its protection by epigallo-catechin gallate.
abstract: We found a novel procaspase-3 activating cascade mediated by lysosomal enzyme. The activating enzyme of procaspase-3, named lysoapoptase having the molecular weight of 78kDa was determined to be a lactoferrin located in the lysosome. Recombinant lactoferrin accelerated the processing of procaspase-3 to form active caspase-3 in vitro. D-Galactosamine is a well-known inducer of hepatocyte apoptosis. The caspase-3 which plays a common central role in the final step of various apoptosis cascades, was dramatically increased in the cytoplasm by the d-galactosamine administration in vivo. When D-galactosamine was administrated as a death signal in vivo, the lysosomal lactoferrin was released into the cytoplasm and procaspase-3 located in the cytoplasm was processed to form active caspase-3. The cotreatment of epigallo-catechin gallate resulted in the complete protection of the hepatocyte apoptosis suppressing the increases of caspase-3 in the cytoplasm. The caspase-3 activity was also inhibited directly by the epigallo-catechin gallate. Therefore, all apoptosis cascades mediated by caspase-3 should be suppressed by epigallo-catechin gallate. The caspase-3 activity was not only directly inhibited by epigallo-catechin gallate in vitro, but the release of lactoferrin from the lysosomes into the cytoplasm was also suppressed by epigallo-catechin gallate treatment in vivo. Therefore, the apoptosis induction was suppressed at the two successive steps by cotreatment of epigallo-catechin gallate in vivo.
authors.affiliation: Institute for Health Sciences, Tokushima Bunri University, 180 Bouji, Nishihama, Yamashiro-cho, Tokushima-shi, Tokushima-ken 770-8514, Japan. katunuma@tokushima.bunri-u.ac.jp
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Katunuma
authors.forename: Etsuko
authors.initials: E
authors.lastname: Murata
authors.forename: Quang T
authors.initials: QT
authors.lastname: Le
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohashi
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000302:isolation & purification / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D005688:Galactosamine / Q000633:toxicity; D007700:Kinetics; D007781:Lactoferrin / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008247:Lysosomes / Q000201:enzymology*; D008954:Models, Biological; D011480:Protease Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D011480:Protease Inhibitors; D011994:Recombinant Proteins; D005688:Galactosamine; D002392:Catechin; C045651:epigallocatechin gallate; D007781:Lactoferrin; D053148:Caspase 3; D020169:Caspases