文章：

靶向肾细胞癌中的NPC1

Targeting NPC1 in Renal Cell Carcinoma

原文发布日期：25 January 2024

DOI: 10.3390/cancers16030517

类型: Article

开放获取: 是

英文摘要：

Rapidly proliferating cancer cells have a greater requirement for cholesterol than normal cells. Tumor cells are largely dependent on exogenous lipids given that their growth requirements are not fully met by endogenous pathways. Our current study shows that ccRCC cells have redundant mechanisms of cholesterol acquisition. We demonstrate that all major lipoproteins (i.e., LDL, HDL, and VLDL) have a comparable ability to support the growth of ccRCC cells and are equally effective in counteracting the antitumor activities of TKIs. The intracellular trafficking of exogenous lipoprotein-derived cholesterol appears to be distinct from the movement of endogenously synthesized cholesterol. De novo synthetized cholesterol is transported from the endoplasmic reticulum directly to the plasma membrane and to the acyl-CoA: cholesterol acyltransferase, whereas lipoprotein-derived cholesterol is distributed through the NPC1-dependent endosomal trafficking system. Expression of NPC1 is increased in ccRCC at mRNA and protein levels, and high expression of NPC1 is associated with poor prognosis. Our current findings show that ccRCC cells are particularly sensitive to the inhibition of endolysosomal cholesterol export and underline the therapeutic potential of targeting NPC1 in ccRCC.

摘要翻译： 

快速增殖的癌细胞对胆固醇的需求远高于正常细胞。由于内源性合成途径无法完全满足其生长需求，肿瘤细胞在很大程度上依赖于外源性脂质摄取。本研究揭示透明细胞肾细胞癌（ccRCC）细胞具有冗余的胆固醇获取机制。实验证明所有主要脂蛋白（包括低密度脂蛋白、高密度脂蛋白和极低密度脂蛋白）均能同等程度地支持ccRCC细胞生长，并具有相似的对抗酪氨酸激酶抑制剂抗肿瘤活性的能力。外源性脂蛋白来源胆固醇的细胞内运输途径与内源性合成胆固醇的转运机制存在显著差异：新合成的胆固醇从内质网直接运输至质膜及酰基辅酶A-胆固醇酰基转移酶，而脂蛋白来源胆固醇则通过NPC1依赖的内体运输系统进行分布。在ccRCC中，NPC1在mRNA和蛋白水平的表达均显著上调，且其高表达与不良预后密切相关。本研究结果表明ccRCC细胞对内溶酶体胆固醇输出的抑制具有特殊敏感性，这为靶向NPC1治疗ccRCC提供了潜在的治疗策略。

原文链接：

Targeting NPC1 in Renal Cell Carcinoma