PuSH - Publication Server of Helmholtz Zentrum München: Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells.

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Sun, Y.* ; Berleth, N.* ; Wu, W.* ; Schlütermann, D.* ; Deitersen, J.* ; Stuhldreier, F.* ; Berning, L.* ; Friedrich, A.* ; Akgün, S.* ; Mendiburo, M.J.* ; Wesselborg, S.* ; Conrad, M. ; Berndt, C.* ; Stork, B.*

Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells.

Cell Death Dis. 12:1028 (2021)

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Ferroptosis is a form of regulated cell death that emerges to be relevant for therapy-resistant and dedifferentiating cancers. Although several lines of evidence suggest that ferroptosis is a type of autophagy-dependent cell death, the underlying molecular mechanisms remain unclear. Fin56, a type 3 ferroptosis inducer, triggers ferroptosis by promoting glutathione peroxidase 4 (GPX4) protein degradation via a not fully understood pathway. Here, we determined that Fin56 induces ferroptosis and autophagy in bladder cancer cells and that Fin56-triggered ferroptosis mechanistically depends on the autophagic machinery. Furthermore, we found that autophagy inhibition at different stages attenuates Fin56-induced oxidative stress and GPX4 degradation. Moreover, we investigated the effects of Fin56 in combination with Torin 2, a potent mTOR inhibitor used to activate autophagy, on cell viability. We found that Fin56 synergizes with Torin 2 in cytotoxicity against bladder cancer cells. Collectively, our findings not only support the concept that ferroptosis is a type of autophagy-dependent cell death but imply that the combined application of ferroptosis inducers and mTOR inhibitors is a promising approach to improve therapeutic options in the treatment of bladder cancer.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cystine/glutamate Antiporter; Oxidative Stress; System X(c)(-); Death; Mechanisms; Phosphorylation; Metabolism; Storage; Target; Atg13

ISSN (print) / ISBN 2041-4889

e-ISSN 2041-4889

Journal Cell Death & Disease

Quellenangaben Volume: 12, Issue: 11, Article Number: 1028

Publisher Nature Publishing Group

Publishing Place Campus, 4 Crinan St, London, N1 9xw, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Metabolism and Cell Death (MCD)

Grants EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
Deutsche Forschungsgemeinschaft (German Research Foundation)