Cholesterol auxotrophy as a targetable vulnerability in clear cell renal cell carcinoma

Romain Riscal, Caroline J Bull, Mattias Johansson, Nicholas John Timpson, Emma E Vincent*, M Celeste Simon*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets (LDs) 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 performed 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.
Original languageEnglish
JournalCancer Discovery
Early online date8 Jul 2021
DOIs
Publication statusE-pub ahead of print - 8 Jul 2021

Bibliographical note

This research was funded in whole, or in part, by The Wellcome Trust 202802/Z/16/Z. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Structured keywords

  • ICEP

Keywords

  • SCARB1
  • HDL
  • ROS
  • PI3K/AKT
  • ccRCC

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