Intracellular cholesterol biosynthesis in enchondroma and chondrosarcoma.
Intracellular cholesterol biosynthesis in enchondroma and chondrosarcoma.
复制标题
内生软骨瘤和软骨肉瘤中的细胞内胆固醇生物合成。
DOI：
10.1172/jci.insight.127232
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发表时间：
2019
期刊：
影响因子：
8
通讯作者：
Alman,BenjaminA
中科院分区：
文献类型：
--
作者：
Zhang,Hongyuan;Wei,Qingxia;Tsushima,Hidetoshi;Puviindran,Vijitha;Tang,YuningJ;Pathmanapan,Sinthu;Poon,Raymond;Ramu,Eyal;Al-Jazrawe,Mushriq;Wunder,Jay;Alman,BenjaminA
软骨内生性瘤和软骨肉瘤是最常见的良恶性软骨肿瘤。异柠檬酸脱氢酶1和2 （IDH1/2）的突变存在于大多数这些肿瘤中。我们对Col2a1Cre的软骨细胞进行了RNA-seq分析；Idh1LSL/+动物，发现胆固醇合成途径中隐含的基因在突变的软骨细胞中显著上调。在IDH1突变小鼠中，我们通过有条件地删除甾醇调节元件结合蛋白裂解激活蛋白（一种激活细胞内胆固醇合成的蛋白）来检测抑制细胞内胆固醇生物合成对软骨瘤形成的表型影响。我们发现在缺少SCAP的动物中很少出现内生软骨瘤。此外，在软骨肉瘤中，细胞内胆固醇合成的药物抑制在体外显著降低了软骨肉瘤细胞的活力，在体内抑制了肿瘤的生长。综上所述，这些数据表明细胞内胆固醇合成是内生纤维瘤和软骨肉瘤的潜在治疗靶点。
Enchondroma and chondrosarcoma are the most common benign and malignant cartilaginous neoplasms. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are present in the majority of these tumors. We performed RNA-seq analysis on chondrocytes from Col2a1Cre;Idh1LSL/+ animals and found that genes implied in the cholesterol synthesis pathway were significantly upregulated in the mutant chondrocytes. We examined the phenotypic effect of inhibiting intracellular cholesterol biosynthesis on enchondroma formation by conditionally deleting sterol regulatory element–binding protein cleavage-activating protein (SCAP), a protein activating intracellular cholesterol synthesis, in IDH1 mutant mice. We found fewer enchondromas in animals lacking SCAP. Furthermore, in chondrosarcomas, pharmacological inhibition of intracellular cholesterol synthesis substantially reduced chondrosarcoma cell viability in vitro and suppressed tumor growth in vivo. Taken together, these data suggest that intracellular cholesterol synthesis is a potential therapeutic target for enchondromas and chondrosarcomas.
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