Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells
Jianping He,
Abigail M. Abikoye,
Brett P. McLaughlin,
Ryan S. Middleton,
Ryan Sheldon,
Russell G. Jones,
Zachary T. Schafer
Affiliations
Jianping He
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA; Boler-Parseghian Center for Rare & Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA
Abigail M. Abikoye
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA; Boler-Parseghian Center for Rare & Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA
Brett P. McLaughlin
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA; Boler-Parseghian Center for Rare & Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA
Ryan S. Middleton
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA; Boler-Parseghian Center for Rare & Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA
Ryan Sheldon
Metabolomics and Bioenergetics Core, Van Andel Institute, Grand Rapids, MI 49503, USA
Russell G. Jones
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
Zachary T. Schafer
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA; Boler-Parseghian Center for Rare & Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA; Corresponding author
Summary: 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.
