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

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.

Ferroptosis-related long non-coding RNA signature predicts the prognosis of bladder cancer

“…Pretreatment with FG-4592, an inhibitor of prolyl hydroxylase of HIF, reduces renal injury via AKT/GSK-3β-mediated activation of Nrf2 in advanced stages of ferroptosis [ 32 ]. In addition, Yadong Sun et al reported that cancer spheroids proliferate using mammalian targets of rapamycin (mTOR) and utilize the lipid peroxidase GPX4 against ferroptosis [ 33 ].…”

A Novel Prognostic Signature Based on Ferroptosis-Related Genes Predicts the Prognosis of Patients With Advanced Bladder Urothelial Carcinoma

“…It has been reported that FRGs are involved in the regulation of drug-induced ferroptosis in BLCA ( 11 ). Additionally, FRG-related inducers have been found to suppress BC with the help of mTOR inhibitors ( 19 ). Recently, ferroptosis participates in the inhibition of cell cycle in BC by obstructing the G0/G1 phase ( 11 ).…”

Application of Regulatory Cell Death in Cancer: Based on Targeted Therapy and Immunotherapy

“…Sun et al. showed that FIN56 can induce ferroptosis in bladder cancer cells and can be enhanced by combination with the mTOR inhibitor, Torin 2 ( 143 ). Zhang et al.…”