title: Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase.
abstract: Lysosomal membrane permeabilization and subsequent cell death may prove useful in cancer treatment, provided that cancer cell lysosomes can be specifically targeted. Here, we identify acid sphingomyelinase (ASM) inhibition as a selective means to destabilize cancer cell lysosomes. Lysosome-destabilizing experimental anticancer agent siramesine inhibits ASM by interfering with the binding of ASM to its essential lysosomal cofactor, bis(monoacylglycero)phosphate. Like siramesine, several clinically relevant ASM inhibitors trigger cancer-specific lysosomal cell death, reduce tumor growth in vivo, and revert multidrug resistance. Their cancer selectivity is associated with transformation-associated reduction in ASM expression and subsequent failure to maintain sphingomyelin hydrolysis during drug exposure. Taken together, these data identify ASM as an attractive target for cancer therapy.
authors.affiliation: Department of Cell Death and Metabolism, Danish Cancer Society Research Center (DCRC), DK-2100 Copenhagen, Denmark.
authors.forename: Nikolaj H T
authors.initials: NH
authors.lastname: Petersen
authors.forename: Ole D
authors.initials: OD
authors.lastname: Olsen
authors.forename: Line
authors.initials: L
authors.lastname: Groth-Pedersen
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Ellegaard
authors.forename: Mesut
authors.initials: M
authors.lastname: Bilgin
authors.forename: Susanne
authors.initials: S
authors.lastname: Redmer
authors.forename: Marie S
authors.initials: MS
authors.lastname: Ostenfeld
authors.forename: Danielle
authors.initials: D
authors.lastname: Ulanet
authors.forename: Tobias H
authors.initials: TH
authors.lastname: Dovmark
authors.forename: Andreas
authors.initials: A
authors.lastname: Lønborg
authors.forename: Signe D
authors.initials: SD
authors.lastname: Vindeløv
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
authors.forename: Christoph
authors.initials: C
authors.lastname: Arenz
authors.forename: Christer S
authors.initials: CS
authors.lastname: Ejsing
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirkegaard
authors.forename: Mikkel
authors.initials: M
authors.lastname: Rohde
authors.forename: Jesper
authors.initials: J
authors.lastname: Nylandsted
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättelä
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000633:toxicity; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D013107:Sphingolipids / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000494:pharmacology / Q000633:toxicity; D024505:Tocopherols / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D007211:Indoles; C109644:Lu 28-179; D013107:Sphingolipids; D013141:Spiro Compounds; D013108:Sphingomyelin Phosphodiesterase; D024505:Tocopherols