Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation

Autophagy. 2008 May;4(4):487-99. doi: 10.4161/auto.5774. Epub 2008 Feb 22.

Abstract

A sigma-2 receptor ligand siramesine induces lysosomal leakage and cathepsin-dependent death of cancer cells in vitro and displays potent anti-cancer activity in vivo. The mechanism by which siramesine destabilizes lysosomes is, however, unknown. Here, we show that siramesine induces a rapid rise in the lysosomal pH that is followed by lysosomal leakage and dysfunction. The rapid accumulation of siramesine into cancer cell lysosomes, its ability to destabilize isolated lysosomes, and its chemical structure as an amphiphilic amine indicate that it is a lysosomotropic detergent. Notably, siramesine triggers also a substantial Atg6- and Atg7-dependent accumulation of autophagosomes that is associated with a rapid and sustained inhibition of mammalian target of rapamycin complex 1 (mTORC1; an inhibitor of autophagy). Siramesine fails, however, to increase the degradation rate of long-lived proteins. Thus, the massive accumulation of autophagosomes is likely to be due to a combined effect of activation of autophagy signaling and decreased autophagosome turnover. Importantly, pharmacological and RNA interference-based inhibition of autophagosome formation further sensitizes cancer cells to siramesine-induced cytotoxicity. These data identify siramesine as a lysosomotropic detergent that triggers cell death via a direct destabilization of lysosomes and cytoprotection by inducing the accumulation of autophagosomes. Threrefore, the combination of siramesine with inhibitors of autophagosome formation appears as a promising approach for future cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism*
  • Autophagy / physiology*
  • Cell Line, Tumor
  • Cytoprotection*
  • Detergents / chemistry
  • Detergents / metabolism*
  • Female
  • Humans
  • Hydrogen-Ion Concentration
  • Indoles / chemistry
  • Indoles / metabolism*
  • Intracellular Membranes / metabolism
  • Lysosomes / metabolism*
  • Lysosomes / ultrastructure
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Molecular Structure
  • Multiprotein Complexes
  • Phagosomes / metabolism*
  • Phospholipids / metabolism
  • Proteins
  • Receptors, sigma / metabolism
  • Signal Transduction / physiology
  • Spiro Compounds / chemistry
  • Spiro Compounds / metabolism*
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Detergents
  • Indoles
  • Lu 28-179
  • Multiprotein Complexes
  • Phospholipids
  • Proteins
  • Receptors, sigma
  • Spiro Compounds
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1