Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer.

Autor: Liu W; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA., Chakraborty B; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA., Safi R; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA., Kazmin D; Emory Vaccine Center, Emory University, Atlanta, GA, 30322, USA., Chang CY; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA., McDonnell DP; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA. donald.mcdonnell@duke.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Aug 24; Vol. 12 (1), pp. 5103. Date of Electronic Publication: 2021 Aug 24.
DOI: 10.1038/s41467-021-25354-4
Abstrakt: Hypercholesterolemia and dyslipidemia are associated with an increased risk for many cancer types and with poor outcomes in patients with established disease. Whereas the mechanisms by which this occurs are multifactorial we determine that chronic exposure of cells to 27-hydroxycholesterol (27HC), an abundant circulating cholesterol metabolite, selects for cells that exhibit increased cellular uptake and/or lipid biosynthesis. These cells exhibit substantially increased tumorigenic and metastatic capacity. Notably, the metabolic stress imposed upon cells by the accumulated lipids requires sustained expression of GPX4, a negative regulator of ferroptotic cell death. We show that resistance to ferroptosis is a feature of metastatic cells and further demonstrate that GPX4 knockdown attenuates the enhanced tumorigenic and metastatic activity of 27HC resistant cells. These findings highlight the general importance of ferroptosis in tumor growth and metastasis and suggest that dyslipidemia/hypercholesterolemia impacts cancer pathogenesis by selecting for cells that are resistant to ferroptotic cell death.
(© 2021. The Author(s).)
Databáze: MEDLINE
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