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- W4225763441 abstract "Abstract Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses based on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell-cycle arrest, apoptosis, elevated intracellular reactive oxygen species levels, and decreased PI3K/AKT signaling. Collectively, we reveal a cholesterol dependency in ccRCC and implicate SCARB1 as a novel therapeutic target for treating kidney cancer. Significance: We demonstrate that ccRCC cells are auxotrophic for exogenous cholesterol to maintain PI3K/AKT signaling pathway and ROS homeostasis. Blocking cholesterol import through the HDL transporter SCARB1 compromises ccRCC cell survival and tumor growth, suggesting a novel pharmacologic target for this disease. This article is highlighted in the In This Issue feature, p. 2945" @default.
- W4225763441 created "2022-05-05" @default.
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- W4225763441 date "2021-07-08" @default.
- W4225763441 modified "2023-10-03" @default.
- W4225763441 title "Cholesterol Auxotrophy as a Targetable Vulnerability in Clear Cell Renal Cell Carcinoma" @default.
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- W4225763441 doi "https://doi.org/10.1158/2159-8290.cd-21-0211" @default.
- W4225763441 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34244212" @default.
- W4225763441 hasPublicationYear "2021" @default.
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