Cell Death and Disease (Oct 2021)

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

  • Yadong Sun,
  • Niklas Berleth,
  • Wenxian Wu,
  • David Schlütermann,
  • Jana Deitersen,
  • Fabian Stuhldreier,
  • Lena Berning,
  • Annabelle Friedrich,
  • Seda Akgün,
  • María José Mendiburo,
  • Sebastian Wesselborg,
  • Marcus Conrad,
  • Carsten Berndt,
  • Björn Stork

DOI
https://doi.org/10.1038/s41419-021-04306-2
Journal volume & issue
Vol. 12, no. 11
pp. 1 – 14

Abstract

Read online

Abstract 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.