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Research Paper

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

Marie Stampe Ostenfeld, Maria Høyer-Hansen, Lone Bastholm, Nicole Fehrenbacher, Ole Dines Olsen, Line Groth-Pedersen, Pietri Puustinen, Thomas Kirkegaard-Sørensen, Jesper Nylandsted, Thomas Farkas and Marja Jäättelä

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A σ-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.

Authors

Marie Stampe Ostenfeld

Danish Cancer Society

Maria Høyer-Hansen

Danish Cancer Society

Lone Bastholm

copenhagen university

Nicole Fehrenbacher

Danish Cancer Society

Ole Dines Olsen

Danish Cancer Society

Line Groth-Pedersen

Danish Cancer Society

Pietri Puustinen

Danish Cancer Society

Thomas Kirkegaard-Sørensen

Danish Cancer Society

Jesper Nylandsted

Danish Cancer Society

Thomas Farkas

Danish Cancer Society

Marja Jäättelä

Danish Cancer Society

Purchase article for $19

Subscribe to this journal for $99/year