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National Institute of Environmental Health Sciences

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Publication Detail

Title: Cholesterol Auxotrophy as a Targetable Vulnerability in Clear Cell Renal Cell Carcinoma.

Authors: Riscal, Romain; Bull, Caroline J; Mesaros, Clementina; Finan, Jennifer M; Carens, Madeleine; Ho, Elaine S; Xu, Jimmy P; Godfrey, Jason; Brennan, Paul; Johansson, Mattias; Purdue, Mark P; Chanock, Stephen J; Mariosa, Daniela; Timpson, Nicholas J; Vincent, Emma E; Keith, Brian; Blair, Ian A; Skuli, Nicolas; Simon, M Celeste

Published In Cancer Discov, (2021 Dec 01)

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.

PubMed ID: 34244212 Exiting the NIEHS site

MeSH Terms: Carcinoma, Renal Cell*/pathology; Cell Line, Tumor; Cell Proliferation/genetics; Cholesterol/therapeutic use; Humans; Kidney Neoplasms*/pathology; Phosphatidylinositol 3-Kinases/metabolism

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