Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells

• Published in: iScience Vol. 26; no. 6; p. 106827
• Main Authors: He, Jianping, Abikoye, Abigail M., McLaughlin, Brett P., Middleton, Ryan S., Sheldon, Ryan, Jones, Russell G., Schafer, Zachary T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.06.2023; Elsevier
• Subjects: Cancer; Cell biology; Cell biology; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.106827

Cancer cells often acquire resistance to cell death programs induced by loss of integrin-mediated attachment to extracellular matrix (ECM). Given that adaptation to ECM-detached conditions can facilitate tumor progression and metastasis, there is significant interest in effective elimination of ECM-detached cancer cells. Here, we find that ECM-detached cells are remarkably resistant to the induction of ferroptosis. Although alterations in membrane lipid content are observed during ECM detachment, it is instead fundamental changes in iron metabolism that underlie resistance of ECM-detached cells to ferroptosis. More specifically, our data demonstrate that levels of free iron are low during ECM detachment because of changes in both iron uptake and iron storage. In addition, we establish that lowering the levels of ferritin sensitizes ECM-detached cells to death by ferroptosis. Taken together, our data suggest that therapeutics designed to kill cancer cells by ferroptosis may be hindered by lack of efficacy toward ECM-detached cells. [Display omitted] •ECM-detached cells are resistant to ferroptosis induction•Loss of Yap-mediated ACSL4 does not cause ferroptosis resistance during detachment•ECM detachment causes alterations in iron uptake•Alterations in NRF2/FTH1 contribute to ferroptosis resistance during ECM detachment Cell biology; Cancer