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

• Authors: Wen Liu, Duke University; Binita Chakraborty, Duke University; Rachid Safi, Duke University; Dmitri Kazmin, Emory University; Ching-Yi Chang, Duke University; Donald P McDonnell, Duke University
• Journal Title: NATURE COMMUNICATIONS
• Volume: Volume 12, Number 1
• Publisher: NATURE PORTFOLIO | 2021-08-24, Pages 5103-5103
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41467-021-25354-4
• Subjects: Health Sciences, Pharmacology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; BREAST-CANCER; STATIN USE; CARDIOVASCULAR-DISEASE; CELL-DEATH; 27-HYDROXYCHOLESTEROL; METABOLISM; OXYSTEROLS; RECEPTOR; OBESITY; RISK

Abstract

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.