Targeted reduction of cholesterol uptake in cholesterol-addicted lymphoma cells blocks turnover of oxidized lipids to cause ferroptosis

• Published in: The Journal of biological chemistry Vol. 296; p. 100100
• Main Authors: Rink, Jonathan S., Lin, Adam Yuh, McMahon, Kaylin M., Calvert, Andrea E., Yang, Shuo, Taxter, Tim, Moreira, Jonathan, Chadburn, Amy, Behdad, Amir, Karmali, Reem, Thaxton, C. Shad, Gordon, Leo I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; cholesterol; Cholesterol - genetics; Cholesterol - metabolism; Ferroptosis; glutathione peroxidase 4 (GPX4); high-density lipoprotein (HDL); Humans; Jurkat Cells; lipid peroxidation; lymphoma; Lymphoma - genetics; Lymphoma - metabolism; Lymphoma - pathology; Mice; Mice, SCID; nanotechnology; Neoplasm Proteins - metabolism; Oxidation-Reduction; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; scavenger receptor type B1 (SCARB1); Scavenger Receptors, Class B - genetics; Scavenger Receptors, Class B - metabolism; U937 Cells; ALK; SCARB1; ABC; DLBCL; ferroptosis; DiI; IHC; FL; INSIG1; scavenger receptor type B1 (SCARB1); Hepes; NF-kB; AuNP; ALCL; BL; FACS; DFO; HSD17B7; STR; HDL; LDL; TFF; FBS; nanotechnology; cholesterol; L-OH; GC; LDLR; high-density lipoprotein (HDL); DPPC; PDP PE; PBS; L-OOH; glutathione peroxidase 4 (GPX4); GPX4; HMGCS1; PDX; lymphoma; HDL NPs; lipid peroxidation; SREBP-1a; BCR; SQLE; HCM; MPER; C11-BODIPY; PI; DHCR7
• DOI: 10.1074/jbc.RA120.014888
• ISSN: 0021-9258; 1083-351X

Normal human cells can either synthesize cholesterol or take it up from lipoproteins to meet their metabolic requirements. In some malignant cells, de novo cholesterol synthesis genes are transcriptionally silent or mutated, meaning that cholesterol uptake from lipoproteins is required for survival. Recent data suggest that lymphoma cells dependent upon lipoprotein-mediated cholesterol uptake are also subject to ferroptosis, an oxygen- and iron-dependent cell death mechanism triggered by accumulation of oxidized lipids in cell membranes unless the lipid hydroperoxidase, glutathione peroxidase 4 (GPX4), reduces these toxic lipid species. To study mechanisms linking cholesterol uptake with ferroptosis and determine the potential role of the high-density lipoprotein (HDL) receptor as a target for cholesterol depleting therapy, we treated lymphoma cell lines known to be sensitive to the reduction of cholesterol uptake with HDL-like nanoparticles (HDL NPs). HDL NPs are a cholesterol-poor ligand that binds to the receptor for cholesterol-rich HDLs, scavenger receptor type B1 (SCARB1). Our data reveal that HDL NP treatment activates a compensatory metabolic response in treated cells toward increased de novo cholesterol synthesis, which is accompanied by nearly complete reduction in expression of GPX4. As a result, oxidized membrane lipids accumulate, leading to cell death through a mechanism consistent with ferroptosis. We obtained similar results 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, resulting in cancer cell death by a mechanism consistent with ferroptosis.