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

Autor: 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.
Rok vydání: 2021
Předmět:
Zdroj: Cell Death & Disease
Cell Death and Disease, Vol 12, Iss 11, Pp 1-14 (2021)
Cell Death Dis. 12:1028 (2021)
ISSN: 2041-4889
Popis: 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.
Databáze: OpenAIRE
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