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.
Cancer discovery. 2021 Jul 08 [Epub ahead of print]
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
BRB, The University of Pennsylvania School of Medicine., Bristol Medical School, University of Bristol., Pharmacology, University of Pennsylvania., Cell, Developmental and Cancer Biology, Oregon Health and Science University., Abramson Family Cancer Research Institute, University of Pennsylvania., University of Pennsylvania., Genetic Epidemiology, International Agency For Research On Cancer., Division of Cancer Epidemiology and Genetics, National Cancer Institute., Genetic Epidemiology Group, Section of Genetics, International Agency For Research On Cancer., Department Social Medicine, University of Bristol., Cellular and Molecular Medicine and MRC Integrative Epidemiology Unit, Population Health Science, Univeristy of Bristol., Tumor Microenvironment and Metastasis, University of Pennsylvania., Department of Systems Pharmacology and Translational Therapeutics, Center for Cancer Pharmacology, Perelman School of Medicine, University of Pennsylvania., Hematology-Oncology, Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania., Abramson Family Cancer Research Institute, University of Pennsylvania .