Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase

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  • Nikolaj H T Petersen, Department of Cell Death and Metabolism, Danish Cancer Society Research Center (DCRC), DK-2100 Copenhagen, Denmark., Danmark
  • Ole D Olsen, Danmark
  • Line Groth-Pedersen, Danmark
  • Anne-Marie Ellegaard, Danmark
  • Mesut Bilgin, Danmark
  • Susanne Redmer, Danmark
  • Marie Stampe Ostenfeld, Danmark
  • Danielle Ulanet, Danmark
  • Tobias H Dovmark, Danmark
  • Andreas Lønborg, Danmark
  • Signe D Vindeløv, Danmark
  • Douglas Hanahan, Danmark
  • Christoph Arenz, Danmark
  • Christer S Ejsing
  • ,
  • Thomas Kirkegaard, Danmark
  • Mikkel Rohde, Danmark
  • Jesper Nylandsted, Danmark
  • Marja Jäättelä

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.

OriginalsprogEngelsk
TidsskriftCancer Cell
Vol/bind24
Nummer3
Sider (fra-til)379-93
Antal sider15
ISSN1535-6108
DOI
StatusUdgivet - 9 sep. 2013

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