Project Details
Projekt
Targeting selenocysteine metabolism to improve ferroptosis inducing strategies
Subject Area
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461445936
Ferroptosis is a cell death modality that has attracted considerable interest as a means to eradicate specific tumor lineages addicted to the activity of the selenoprotein GPX4. GPX4 inhibits ferroptosis by preventing the accumulation of phospholipid hydroperoxides, ultimately rendering it a bona fide target for inhibitor development to induce cell death. Currently, selective inhibitors of GPX4 that effectively work in vivo are missing. Specific features of the enzyme have hindered the development of ferroptosis inducing strategies so far. This is acknowledged today as one of the major bottlenecks to translate ferroptosis inducing strategies to pre-clinical models and ultimately cancer patients that could benefit from this strategy. In the present application we propose to explore the potential to target the metabolism of the rare amino acid selenocysteine (Sec) as a way to indirectly impact the activity of GPX4. Our preliminary data using model cancer entities strongly suggest that this approach can be successfully implemented. Hence, we plan to use a combination of in vitro and in vivo models combined with genetic screens to understand in detail the mechanisms involved in mobilizing Sec on a cellular level. Additionally, by structurally and biochemically characterizing selected members of the Sec pathway we will be able provide important molecular insights into selenium utilization and initiate the identification of novel small molecules targeting this pathway. Our studies will be of paramount importance to develop novel strategies aiming to induce ferroptosis and will provide an initial step towards translating them for therapeutic use.
DFG Programme
Priority Programmes
