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bioRxiv · 10.1101/2022.09.23.509253

Reprogramming of Iron Metabolism Confers Ferroptosis Resistance in ECM-Detached Cells

He, J.·Abikoye, A. M.·McLaughlin, B. P.·Middleton, R. S.·Sheldon, R.·Jones, R. G.·Schafer, Z. T.
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Abstract

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. While 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 due to changes in both iron uptake and iron storage. In addition, we establish that lowering the levels of iron storage proteins 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 towards ECM-detached cells.

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He, J., Abikoye, A. M., McLaughlin, B. P., Middleton, R. S., Sheldon, R., Jones, R. G., Schafer, Z. T.. 2022-09-25. Reprogramming of Iron Metabolism Confers Ferroptosis Resistance in ECM-Detached Cells. https://doi.org/10.1101/2022.09.23.509253

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