title: Decreased apoptotic response of inclusion-cell disease fibroblasts: a consequence of lysosomal enzyme missorting?
abstract: To better understand the role of lysosomes in apoptosis, we compared the responses to apoptotic stimuli of normal fibroblasts with those of inclusion cells (I-cells), i.e., fibroblasts with impaired function of lysosomal enzymes due to their missorting and ensuing nonlysosomal localization. Although both cell types did undergo apoptosis when exposed to the lysosomotropic detergent MSDH, the redox-cycling quinone naphthazarin, or the protein kinase inhibitor staurosporine, I-cells exerted a markedly decreased response to these agonists than did normal fibroblasts. Furthermore, leupeptin and pepstatin A (inhibitors of cysteine and aspartic proteases, respectively) suppressed staurosporine-induced apoptosis of normal fibroblasts, whereas survival of I-cells was unaffected. These findings give further support for the involvement of lysosomal enzymes in apoptosis and suggest I-cells as a suitable model for studying the role of lysosomes in programmed cell death.
authors.affiliation: Division of Pathology II, Linköping University, Linköping, 58185, Sweden. alex.terman@pat.liu.se
authors.forename: Alexei
authors.initials: A
authors.lastname: Terman
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
authors.forename: Katarina
authors.initials: K
authors.lastname: Kågedal
authors.forename: Karin
authors.initials: K
authors.lastname: Ollinger
authors.forename: Ulf T
authors.initials: UT
authors.lastname: Brunk
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016022:Case-Control Studies; D002403:Cathepsins / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D003902:Detergents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D007223:Infant; D008247:Lysosomes / Q000201:enzymology / Q000473:pathology; D009081:Mucolipidoses / Q000209:etiology / Q000503:physiopathology*; D021381:Protein Transport; D012867:Skin / Q000166:cytology
chemical_list: D003902:Detergents; D004791:Enzyme Inhibitors; D002403:Cathepsins