Some new aspects of erastin-induced ferroptosis in cancer cells

Ferroptosis, a form of regulated cell death (RCD) with unique morphological and biochemical features, has potential in cancer treatment. In this study, erastin (ER)-induced ferroptosis was investigated in cancer cell lines A549, Calu1, and K562. A detailed analysis of the Xc^-/GSH/GPX4 axis showed that glutathione (GSH) production, unlike GPX4 expression, is an important factor in influencing the sensitivity of tumor cells to ER despite oncogenic KRAS expression. Here we show for the first time that ferroptosis is associated with marked condensation of cell nuclei, a morphological change that was previously associated exclusively with apoptosis. Importantly, this phenomenon was observed in all three cell lines. Further, thiourea (TU), a known scavenger of reactive oxygen species (ROS) had a complex effect on ER induced ferroptosis. While TU significantly potentiated ER cytotoxicity and changed the mode of cell death from ferroptotic to apoptotic in A549 and K562 cells, it had a mild protective effect in Calu1 cells without changing the mode of cell death. In conclusion, the results show that Xc^--dependent GHS production affects the sensitivity of oncogenic RAS-expressing tumor cells to ER treatment. ER-induced ferroptosis is associated with nuclear condensation. Further, we identified TU as a compound that can change the form of cell death from ferroptotic to apoptotic in some cancer cells. The latter two findings suggest a previously uncovered proximity of the regulatory pathways of ferroptosis and apoptosis.