| Autor: |
Gaschler, Michael, Andia, Alexander, Liu, Hengrui, Csuka, Joleen, Hurlocker, Brisa, Vaiana, Christopher, Heindel, Daniel, Zuckerman, Dylan, Bos, Pieter, Reznik, Eduard, Ye, Ling, Tyurina, Yulia, Lin, Annie, Shchepinov, Mikhail, Chan, Amy, Peguero-Pereira, Eveliz, Fomich, Maksim, Daniels, Jacob., Bekish, Andrei, Shmanai, Vadim, Kagan, Valerian, Mahal, Lara, Woerpel, K., Stockwell, Brent |
| Zdroj: |
Nature Chemical Biology; May 2018, Vol. 14 Issue: 5 p507-515, 9p |
| Abstrakt: |
Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and structural features necessary for ferroptosis initiation by FINO2. We found that FINO2requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO2does not inhibit system xc–or directly target the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2can initiate a multipronged mechanism of ferroptosis. FINO2is a small molecule that requires the endoperoxide moiety and hydroxyl group to promote ferroptosis through indirect inhibition of GPX4 enzymatic function and direct oxidation of iron, resulting in increased lipid peroxidation. |
| Databáze: |
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