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.
Highlights
Bladder cancer (BC) is the 10th most-common cancer worldwide, with an estimated 549,000 new cases and 200,000 deaths each year [1]
Since cancer cells require higher levels of iron, generate higher levels of reactive oxygen species (ROS), and have an altered lipid metabolism compared with normal cells, they become more susceptible to ferroptosis [11]
Since mammalian target of rapamycin (mTOR) is a central upstream regulator of autophagy [40], It has been reported that one pathway of Fin56-triggered we investigated whether mTOR was involved in Fin56- ferroptosis is executed via glutathione peroxidase 4 (GPX4) degradation [14], but the induced autophagy
Summary
Bladder cancer (BC) is the 10th most-common cancer worldwide, with an estimated 549,000 new cases and 200,000 deaths each year [1]. We investigated if Fin induces GPX4 degradation in the BC cell lines 253J and T24, and—if yes—if this can be blocked by autophagy inhibition We observed that both were the case (Fig. 6D). Since LC3 and SQSTM1/p62 are detected a reduction of Fin56-induced cell death (Fig. 7A), common autophagy markers that participate in various types of confirming that the regulation of GPX4 levels is central to the autophagy, future studies will have to clarify whether Fin induces control of ferroptosis in these cell lines. We demonstrated that Fin treatment leads to ferritin degradation in abolishes the autophagy-dependent part of Fin56-induced ferroptosis (control on the protein level) These data indicate that the sensitivity of 253J and T224 cells to bafilomycin A1 is—at least partially—caused by the Fin56-induced autophagic degradation of GPX4.
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