Caspase-2 protects against ferroptotic cell death

Dawar, S; Benitez, MC; Lim, Y; Dite, TA; Yousef, JM; Thio, N; Garciaz, S; Jackson, TD; Milne, JV; Dagley, LF; Phillips, WA; Kumar, S; Clemons, NJ

Author(s): Dawar, S; Benitez, MC; Lim, Y; Dite, TA; Yousef, JM; Thio, N; Garciaz, S; Jackson, TD; Milne, JV; Dagley, LF; Phillips, WA; Kumar, S; Clemons, NJ;
Details: Publication Year 2024-03-01,Volume 15,Issue #3,Page 182
Journal Title: Cell Death & Disease
Abstract: Caspase-2, one of the most evolutionarily conserved members of the caspase family, is an important regulator of the cellular response to oxidative stress. Given that ferroptosis is suppressed by antioxidant defense pathways, such as that involving selenoenzyme glutathione peroxidase 4 (GPX4), we hypothesized that caspase-2 may play a role in regulating ferroptosis. This study provides the first demonstration of an important and unprecedented function of caspase-2 in protecting cancer cells from undergoing ferroptotic cell death. Specifically, we show that depletion of caspase-2 leads to the downregulation of stress response genes including SESN2, HMOX1, SLC7A11, and sensitizes mutant-p53 cancer cells to cell death induced by various ferroptosis-inducing compounds. Importantly, the canonical catalytic activity of caspase-2 is not required for its role and suggests that caspase-2 regulates ferroptosis via non-proteolytic interaction with other proteins. Using an unbiased BioID proteomics screen, we identified novel caspase-2 interacting proteins (including heat shock proteins and co-chaperones) that regulate cellular responses to stress. Finally, we demonstrate that caspase-2 limits chaperone-mediated autophagic degradation of GPX4 to promote the survival of mutant-p53 cancer cells. In conclusion, we document a novel role for caspase-2 as a negative regulator of ferroptosis in cells with mutant p53. Our results provide evidence for a novel function of caspase-2 in cell death regulation and open potential new avenues to exploit ferroptosis in cancer therapy.
Publisher: Springer Nature
Research Division(s): Advanced Technology And Biology
PubMed ID: 38429264
Publisher's Version: https://doi.org/10.1038/s41419-024-06560-6
Open Access at Publisher's Site: https://doi.org/ 10.1038/s41419-024-06560-6
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-03-04 01:53:13

Last Modified: 2024-03-04 01:53:45