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: Nikolaj H T Petersen, Ole D Olsen, Line Groth-Pedersen, Anne-Marie Ellegaard, Mesut Bilgin, Susanne Redmer, Marie S Ostenfeld, Danielle Ulanet, Tobias H Dovmark, Andreas Lønborg, Signe D Vindeløv, Douglas Hanahan, Christoph Arenz, Christer S Ejsing, Thomas Kirkegaard, Mikkel Rohde, Jesper Nylandsted, Marja Jäättelä
• Journal: Cancer cell (Cancer Cell) Vol. 24 Issue 3 Pg. 379-93 (Sep 09 2013) ISSN: 1878-3686 [Electronic] United States
• PMID: 24029234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• HSP70 Heat-Shock Proteins
• Indoles
• Lu 28-179
• Sphingolipids
• Spiro Compounds
• Sphingomyelin Phosphodiesterase
• Tocopherols

Topics

• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Transformation, Neoplastic (metabolism)
• Drug Resistance, Neoplasm
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology, toxicity)
• Female
• HSP70 Heat-Shock Proteins (genetics, metabolism)
• Humans
• Indoles (pharmacology, toxicity)
• Lysosomes (metabolism)
• Mice
• Mice, Transgenic
• Phenotype
• Sphingolipids (metabolism)
• Sphingomyelin Phosphodiesterase (antagonists & inhibitors)
• Spiro Compounds (pharmacology, toxicity)
• Tocopherols (pharmacology)
• Xenograft Model Antitumor Assays