Sensitization of cancer cells to ferroptosis coincident with cell cycle arrest

Jason Rodencal; Nathan Kim; Andrew He; Veronica L Li; Mike Lange; Jianping He; Amy Tarangelo; Zachary T Schafer; James A Olzmann; Jonathan Z Long; Julien Sage; Scott J Dixon

doi:10.1016/j.chembiol.2023.10.011

Sensitization of cancer cells to ferroptosis coincident with cell cycle arrest

Cell Chem Biol. 2024 Feb 15;31(2):234-248.e13. doi: 10.1016/j.chembiol.2023.10.011. Epub 2023 Nov 13.

Authors

Affiliations

¹ Department of Biology, Stanford University, Stanford, CA 94305, USA.
² Departments of Pediatrics and Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Sarafan ChEM-H, Stanford University, Stanford, CA 94035, USA.
⁴ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁵ Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
⁶ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁷ Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: sjdixon@stanford.edu.

PMID: 37963466
PMCID: PMC10925838 (available on 2025-02-15)
DOI: 10.1016/j.chembiol.2023.10.011

Abstract

Ferroptosis is a non-apoptotic form of cell death that can be triggered by inhibiting the system x_c^- cystine/glutamate antiporter or the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). We have investigated how cell cycle arrest caused by stabilization of p53 or inhibition of cyclin-dependent kinase 4/6 (CDK4/6) impacts ferroptosis sensitivity. Here, we show that cell cycle arrest can enhance sensitivity to ferroptosis induced by covalent GPX4 inhibitors (GPX4i) but not system x_c^- inhibitors. Greater sensitivity to GPX4i is associated with increased levels of oxidizable polyunsaturated fatty acid-containing phospholipids (PUFA-PLs). Higher PUFA-PL abundance upon cell cycle arrest involves reduced expression of membrane-bound O-acyltransferase domain-containing 1 (MBOAT1) and epithelial membrane protein 2 (EMP2). A candidate orally bioavailable GPX4 inhibitor increases lipid peroxidation and shrinks tumor volumes when combined with a CDK4/6 inhibitor. Thus, cell cycle arrest may make certain cancer cells more susceptible to ferroptosis in vivo.

Keywords: CDK4/6; EMP2; MBOAT1; MUFA; PUFA; ferroptosis; iron; lipid peroxidation; p53; palbociclib.

MeSH terms

Cell Cycle Checkpoints
Cell Death
Fatty Acids, Unsaturated / metabolism
Ferroptosis*
Lipid Peroxidation
Neoplasms* / drug therapy
Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism

Substances

Phospholipid Hydroperoxide Glutathione Peroxidase
Fatty Acids, Unsaturated

Abstract

MeSH terms

Substances

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