Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation.
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.
Ostenfeld
Marie Stampe
MS
Apoptosis Department and Centre for Genotoxic Stress Response, Institute for Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
Høyer-Hansen
Maria
M
Bastholm
Lone
L
Fehrenbacher
Nicole
N
Olsen
Ole Dines
OD
Groth-Pedersen
Line
L
Puustinen
Pietri
P
Kirkegaard-Sørensen
Thomas
T
Nylandsted
Jesper
J
Farkas
Thomas
T
Jäättelä
Marja
M
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D019610:Cytoprotection; D003902:Detergents / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000737:chemistry / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D015394:Molecular Structure; D046912:Multiprotein Complexes; D010588:Phagosomes / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D011506:Proteins; D017480:Receptors, sigma / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D003902:Detergents; D007211:Indoles; C109644:Lu 28-179; D046912:Multiprotein Complexes; D010743:Phospholipids; D011506:Proteins; D017480:Receptors, sigma; D013141:Spiro Compounds; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases