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Figure S3 from Cholesterol Auxotrophy as a Targetable Vulnerability in Clear Cell Renal Cell Carcinoma

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posted on 2023-04-03, 23:42 authored by Romain Riscal, Caroline J. Bull, Clementina Mesaros, Jennifer M. Finan, Madeleine Carens, Elaine S. Ho, Jimmy P. Xu, Jason Godfrey, Paul Brennan, Mattias Johansson, Mark P. Purdue, Stephen J. Chanock, Daniela Mariosa, Nicholas J. Timpson, Emma E. Vincent, Brian Keith, Ian A. Blair, Nicolas Skuli, M. Celeste Simon

Figure S3 shows elevated HDL associated metabolites in RCC. Shows also tumor weight and HDL levels of mice fed with cholesterol diet, related to Figure 2.

Funding

National Institutes of Health (NIH)

Foundation for the National Institutes of Health (FNIH)

Damon Runyon Cancer Research Foundation (DRCRF)

Diabetes UK

National Institute of Environmental Health Sciences (NIEHS)

United States Department of Health and Human Services

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World Cancer Research Fund International (WCRF)

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ARTICLE 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. 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

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    Cancer Discovery

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    cancer

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