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Figure S6 from Bile Acid Metabolism Mediates Cholesterol Homeostasis and Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma

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posted on 2024-05-15, 07:20 authored by Romain Riscal, Sarah M. Gardner, Nathan J. Coffey, Madeleine Carens, Clementina Mesaros, Jimmy P. Xu, Yizheng Xue, Leah Davis, Sara Demczyszyn, Austin Vogt, Adam Olia, Jennifer M. Finan, Jason Godfrey, David C. Schultz, Ian A. Blair, Brian Keith, Ronen Marmorstein, Nicolas Skuli, M. Celeste Simon

Figure S6

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Damon Runyon Cancer Research Foundation (DRCRF)

National Institute of General Medical Sciences (NIGMS)

United States Department of Health and Human Services

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National Institute of Environmental Health Sciences (NIEHS)

United States Department of Health and Human Services

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ARTICLE ABSTRACT

Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. Elevated lipid uptake and storage is required for ccRCC cell viability. As stored cholesterol is the most abundant component in ccRCC intracellular lipid droplets, it may also play an important role in ccRCC cellular homeostasis. In support of this hypothesis, ccRCC cells acquire exogenous cholesterol through the high-density lipoprotein receptor SCARB1, inhibition or suppression of which induces apoptosis. Here, we showed that elevated expression of 3 beta-hydroxy steroid dehydrogenase type 7 (HSD3B7), which metabolizes cholesterol-derived oxysterols in the bile acid biosynthetic pathway, is also essential for ccRCC cell survival. Development of an HSD3B7 enzymatic assay and screening for small-molecule inhibitors uncovered the compound celastrol as a potent HSD3B7 inhibitor with low micromolar activity. Repressing HSD3B7 expression genetically or treating ccRCC cells with celastrol resulted in toxic oxysterol accumulation, impaired proliferation, and increased apoptosis in vitro and in vivo. These data demonstrate that bile acid synthesis regulates cholesterol homeostasis in ccRCC and identifies HSD3B7 as a plausible therapeutic target. The bile acid biosynthetic enzyme HSD3B7 is essential for ccRCC cell survival and can be targeted to induce accumulation of cholesterol-derived oxysterols and apoptotic cell death.

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    Cancer Research

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    Keywords

    Drug Discovery TechnologiesNatural productsDrug TargetsGene TechnologiesGenitourinary CancersRenal cancerMetabolismMetabolic pathwaysOncogenes & Tumor SuppressorsTumor Microenvironment

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