MYC癌基因的过表达通过谷氨酰胺代谢在小鼠模型中驱动肾细胞癌。
MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism.
作者信息
Shroff Emelyn H, Eberlin Livia S, Dang Vanessa M, Gouw Arvin M, Gabay Meital, Adam Stacey J, Bellovin David I, Tran Phuoc T, Philbrick William M, Garcia-Ocana Adolfo, Casey Stephanie C, Li Yulin, Dang Chi V, Zare Richard N, Felsher Dean W
机构信息
Division of Medical Oncology, Departments of Medicine and Pathology, and.
Department of Chemistry, Stanford University School of Medicine, Stanford, CA 94305;
出版信息
Proc Natl Acad Sci U S A. 2015 May 26;112(21):6539-44. doi: 10.1073/pnas.1507228112. Epub 2015 May 11.
The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.
MYC癌基因在人类肾细胞癌（RCC）中经常发生突变并过度表达。然而，尚未有关于MYC或任何其他癌基因在肾肿瘤发生起始或维持过程中致病作用的研究。在此，我们通过条件转基因小鼠模型表明，MYC癌基因而非RAS癌基因启动并维持RCC。采用解吸电喷雾电离质谱成像技术获取小鼠RCC样本中代谢物和脂质的化学图谱。基因表达分析显示，小鼠肿瘤模拟了人类RCC。数据表明，MYC诱导的RCC上调了谷氨酰胺分解途径而非糖酵解途径。用双-2-（5-苯乙酰氨基-1,2,4-噻二唑-2-基）乙基硫醚对谷氨酰胺代谢进行药理抑制可阻碍MYC介导的RCC肿瘤进展。我们的研究表明，MYC过表达导致RCC，并指出抑制谷氨酰胺代谢是治疗该疾病的一种潜在治疗方法。
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