肾透明细胞癌
胆固醇
生物
PI3K/AKT/mTOR通路
细胞生长
肝X受体
癌症研究
胆固醇逆向转运
氧甾醇
内科学
细胞凋亡
脂蛋白
内分泌学
生物化学
肾细胞癌
医学
核受体
转录因子
基因
作者
Romain Riscal,Caroline J. Bull,Clementina Mesaros,Jennifer M. Finan,Madeleine Carens,Elaine Lynn-Ee Ho,Jimmy Xu,Jason T. Godfrey,Paul Brennan,Mikael Johansson,Mark P. Purdue,Stephen J. Chanock,Daniela Mariosa,Nicholas J. Timpson,Emma E. Vincent,Brian Keith,Ian A. Blair,Nicolas Skuli,Michal Simon
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2021-07-08
卷期号:11 (12): 3106-3125
被引量:21
标识
DOI:10.1158/2159-8290.cd-21-0211
摘要
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
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