ABSTRACT
Normal human cells can either synthesize or uptake cholesterol from lipoproteins to meet their metabolic requirements. Some malignant cells absolutely require cholesterol uptake from lipoproteins for survival because de novo cholesterol synthesis genes are transcriptionally silent or mutated. Recent data suggest that lymphoma cells dependent upon lipoprotein-mediated cholesterol uptake are also dependent on the expression of the lipid hydroperoxidase enzyme glutathione peroxidase 4 (GPX4) to prevent cell death by ferroptosis. Ferroptosis is an oxygen-and iron-dependent cell death mechanism that results from the accumulation of oxidized lipids in cell membranes. To study mechanisms linking cholesterol uptake with ferroptosis, we employed lymphoma cell lines known to be sensitive to cholesterol uptake depletion and treated them with high-density lipoprotein-like (HDL) nanoparticles (HDL NPs). HDL NPs are a cholesterol-poor ligand of the receptor for cholesterol-rich HDL, scavenger receptor type B-1 (SCARB1). Our data reveal that HDL NP treatment activates a compensatory metabolic response in treated cells favoring de novo cholesterol synthesis, which is accompanied by reduced expression of GPX4. As a result, accumulation of oxidized membrane lipids leads to cell death through a mechanism consistent with ferroptosis. Furthermore, ferroptosis was validated in vivo after systemic administration of HDL NPs in mouse lymphoma xenografts and in primary samples obtained from patients with lymphoma. In summary, targeting SCARB1 with HDL NPs in cholesterol uptake addicted lymphoma cells abolishes GPX4 and cancer cell death ensues through a mechanism consistent with ferroptosis.
Competing Interest Statement
The authors declare the following conflict of interest: C.S.T., K.M.M., and L.I.G. are co-founders of a biotechnology company that licensed the HDL NP technology from Northwestern University. The remaining authors, J.S.R., A.L., A.E.C., S.Y., T.T., J.M., A.C., R.K., and A.B. declare no competing interests.
Footnotes
Financial Support: This work was supported by the Robert H. Lurie Comprehensive Cancer Center Cancer Center Support Grant (RHLCCC CCSG) (LIG, CST) the National Institutes of Health/National Heart, Lung, and Blood Institute for a Vascular Surgery Scientist Training Program grant (T32HL094293) (JSR), the American Society of Hematology Research Training Award for Fellows (AYL), the Department of Defense/Air Force Office of Scientific Research (FA95501310192), the CRN Regenerative Nanomedicine Catalyst Award Program at Northwestern University, and the National Institutes of Health/National Cancer Institute (R01CA167041) (CST) and the Brookstone, Shannahan and Mander Foundations (LIG).
Conflict of Interest Statement: The authors declare the following conflict of interest: C.S.T., K.M.M., and L.I.G. are co-founders of a biotechnology company that licensed the HDL NP technology from Northwestern University. The remaining authors, J.S.R., A.L., A.E.C., S.Y., T.T., J.M., A.C., R.K., and A.B. declare no competing interests.