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][1] [1]: /lookup/volpage/11/2945?iss=12

中文翻译：

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胆固醇营养缺陷型作为透明细胞肾细胞癌的靶向脆弱性


透明细胞肾细胞癌 (ccRCC) 的特点是细胞内含有游离胆固醇和酯化胆固醇的大脂滴；然而，ccRCC 细胞中胆固醇积累的功能意义尚不清楚。令人惊讶的是，我们证明编码胆固醇生物合成酶的基因在 ccRCC 中受到抑制，这表明对外源胆固醇的依赖。基于 31,000 名个体的孟德尔随机化分析表明，循环高密度脂蛋白 (HDL) 胆固醇升高与 ccRCC 风险之间存在因果关系。剥夺 ccRCC 细胞的胆固醇或高密度脂蛋白会损害体外增殖和存活以及体内肿瘤生长；相反，膳食胆固醇升高会促进肿瘤生长。清道夫受体 B1 (SCARB1) 是胆固醇输入所必需的，抑制 SCARB1 足以导致 ccRCC 细胞周期停滞、细胞凋亡、细胞内活性氧水平升高和 PI3K/AKT 信号传导减弱。总的来说，我们揭示了 ccRCC 中的胆固醇依赖性，并暗示 SCARB1 作为治疗肾癌的新治疗靶点。意义：我们证明 ccRCC 细胞对外源性胆固醇营养缺陷，以维持 PI3K/AKT 信号通路和 ROS 稳态。通过 HDL 转运蛋白 SCARB1 阻断胆固醇输入会损害 ccRCC 细胞的存活和肿瘤生长，这表明该疾病有一个新的药理学靶点。本文在本期专题中突出显示，[p. 11]。 2945][1][1]：/lookup/volpage/11/2945?iss=12