title: Attenuation of the lysosomal death pathway by lysosomal cholesterol accumulation.
abstract: In the past decade, lysosomal membrane permeabilization (LMP) has emerged as a significant component of cell death signaling. The mechanisms by which lysosomal stability is regulated are not yet fully understood, but changes in the lysosomal membrane lipid composition have been suggested to be involved. Our aim was to investigate the importance of cholesterol in the regulation of lysosomal membrane permeability and its potential impact on apoptosis. Treatment of normal human fibroblasts with U18666A, an amphiphilic drug that inhibits cholesterol transport and causes accumulation of cholesterol in lysosomes, rescued cells from lysosome-dependent cell death induced by the lysosomotropic detergent O-methyl-serine dodecylamide hydrochloride (MSDH), staurosporine (STS), or cisplatin. LMP was decreased by pretreating cells with U18666A, and there was a linear relationship between the cholesterol content of lysosomes and their resistance to permeabilization induced by MSDH. U18666A did not induce changes in expression or localization of 70-kDa heat shock proteins (Hsp70) or antiapoptotic Bcl-2 proteins known to protect the lysosomal membrane. Induction of autophagy also was excluded as a contributor to the protective mechanism. By using Chinese hamster ovary (CHO) cells with lysosomal cholesterol overload due to a mutation in the cholesterol transporting protein Niemann-Pick type C1 (NPC1), the relationship between lysosomal cholesterol accumulation and protection from lysosome-dependent cell death was confirmed. Cholesterol accumulation in lysosomes attenuates apoptosis by increasing lysosomal membrane stability.
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. hanna.appelqvist@liu.se
authors.forename: Hanna
authors.initials: H
authors.lastname: Appelqvist
authors.forename: Cathrine
authors.initials: C
authors.lastname: Nilsson
authors.forename: Brett
authors.initials: B
authors.lastname: Garner
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brown
authors.forename: Katarina
authors.initials: K
authors.lastname: Kågedal
authors.forename: Karin
authors.initials: K
authors.lastname: Ollinger
mesh_terms: D000577:Amides / Q000494:pharmacology; D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D019610:Cytoprotection / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D020011:Protective Agents / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012694:Serine / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000577:Amides; D000736:Androstenes; D018840:HSP70 Heat-Shock Proteins; D008562:Membrane Glycoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C407126:O-methyl-serine dodecylamide hydrochloride; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D012694:Serine; D002784:Cholesterol; D019311:Staurosporine; D002945:Cisplatin