Cholesterol Auxotrophy as a Targetable Vulnerability in Clear Cell Renal Cell Carcinoma
Riscal R, Bull CJ, Mesaros C, Finan JM, Carens M, Ho ES, Xu JP, Godfrey J, Brennan P, Johansson M, Purdue MP, Chanock SJ, Mariosa D, Timpson NJ, Vincent EE, Keith B, Blair IA, Skuli N, Simon MC
Cancer discovery · 111 citations
How it was studied
- Design
- In vitro/mechanistic study (classified by our AI screen)
- Studied in
- People, plus animal or lab work
- Main outcome
- Clinical events such as disease or death
Who paid for it
- Funding
- Independent funding
- Nonprofit
- Foundation for the National Institutes of Health
- Nonprofit
- Damon Runyon Cancer Research Foundation
- Government
- World Health Organization
- Nonprofit
- Wellcome Trust
- Nonprofit
- World Cancer Research Fund International
- Nonprofit
- Cancer Research UK
- Nonprofit
- Diabetes UK
- Government
- National Institutes of Health
- Government
- National Cancer Institute
- Government
- National Institute of Environmental Health Sciences
- Government
- NCI NIH HHS
- Government
- NIEHS NIH HHS
- Grants
- Damon Runyon Cancer Research Foundation (DRG2326-18); Cancer Research UK (29019); Diabetes UK (17/0005587); Cancer Research UK (C18281 / A29019); National Cancer Institute (R35 CA220483); Wellcome Trust (202802/Z/16/Z); Foundation for the National Institutes of Health (R35CA197602); National Cancer Institute (P01 CA104838); World Cancer Research Fund International (IIG_2019_2009); National Institute of Environmental Health Sciences (P30ES013508); National Institutes of Health (P01CA104838)
Based on 12 listed funder(s).
Publication
- Published
- 2021-07-08 · Cancer Discov · vol. 11 · issue 12 · pp. 3106–3125
- Publisher
- American Association for Cancer Research
- Cited
- 130 citations · more than 98% of similar papers · 6.7× the field average
- Impact
- Top 10% most cited in its field
- References
- 70 works
- Access
- Open access (repository copy)
- Research areas
- Cancer, Lipids, and Metabolism · Renal cell carcinoma treatment · Cholesterol and Lipid Metabolism
- Keywords
- Clear cell renal cell carcinoma, Auxotrophy, Cholesterol, Vulnerability (computing), Renal cell carcinoma, Transporter, Cell, Cell survival, Kidney
- MeSH
- cell line, tumor, humans, carcinoma, renal cell, kidney neoplasms, cholesterol, cell proliferation, phosphatidylinositol 3-kinases
19 authors
From US, GB, FR
- Romain RiscalUniversity of Pennsylvania
- Caroline J. BullUniversity of Bristol
- Clementina MesarosUniversity of the Sciences
- Jennifer M. FinanUniversity of Pennsylvania
- Madeleine CarensUniversity of Pennsylvania
- Elaine S. HoUniversity of the Sciences
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.
Abstract via Europe PMC. Copyright remains with the authors or publisher.
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