Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells.
Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells.
复制标题
DOI：
10.1126/science.1174229
复制
发表时间：
2009-09-18
期刊：
影响因子：
--
通讯作者：
Papadopoulos N
中科院分区：
文献类型：
--
作者：
Yun J;Rago C;Cheong I;Pagliarini R;Angenendt P;Rajagopalan H;Schmidt K;Willson JK;Markowitz S;Zhou S;Diaz LA Jr;Velculescu VE;Lengauer C;Kinzler KW;Vogelstein B;Papadopoulos N
肿瘤进展是由基因突变驱动的，但人们对选择这些突变的环境条件知之甚少。通过研究仅 KRAS 或 BRAF 基因突变状态不同的配对结直肠癌细胞系的转录组，我们发现编码葡萄糖转运蛋白 1 的 GLUT1 是具有 KRAS 或 BRAF 突变的细胞中持续上调的三个基因之一。突变细胞表现出增强的葡萄糖摄取和糖酵解，并在低葡萄糖条件下存活，这些表型都需要 GLUT1 表达。相比之下，当带有野生型 KRAS 等位基因的细胞处于低葡萄糖环境中时，很少有细胞能够存活。大多数存活细胞表达高水平的 GLUT1，其中 4% 的存活细胞获得了新的 KRAS 突变。糖酵解抑制剂 3-溴丙酮酸优先抑制具有 KRAS 或 BRAF 突变的细胞的生长。总之，这些数据表明葡萄糖剥夺可以驱动人类肿瘤中 KRAS 通路突变的获得。
Tumor progression is driven by genetic mutations, but little is known about the environmental conditions that select for these mutations. Studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF genes, we found that GLUT1, encoding glucose transporter-1, was one of three genes consistently upregulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low glucose conditions, phenotypes that all required GLUT1 expression. In contrast, when cells with wild-type KRAS alleles were subjected to a low glucose environment, very few cells survived. Most surviving cells expressed high levels of GLUT1 and 4% of these survivors had acquired new KRAS mutations. The glycolysis inhibitor, 3-bromopyruvate preferentially suppressed the growth of cells with KRAS or BRAF mutations. Together, these data suggest that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors.
登录
查看更多内容
影响因子：
64.8
作者：
Rajagopalan, H;Bardelli, A;Velculescu, VE
通讯作者：
Velculescu, VE
影响因子：
11.2
作者：
Dang, DT;Chen, F;Dang, LH
通讯作者：
Dang, LH
影响因子：
56.9
作者：
FLIER, JS;MUECKLER, MM;LODISH, HF
通讯作者：
LODISH, HF
DOI：
10.1016/j.bbrc.2004.09.047
发表时间：
2004-11-05
影响因子：
3.1
作者：
Ko, YH;Smith, BL;Pedersen, PL
通讯作者：
Pedersen, PL
DOI：
10.1126/science.1164382
发表时间：
2008-09-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Parsons DW;Jones S;Zhang X;Lin JC;Leary RJ;Angenendt P;Mankoo P;Carter H;Siu IM;Gallia GL;Olivi A;McLendon R;Rasheed BA;Keir S;Nikolskaya T;Nikolsky Y;Busam DA;Tekleab H;Diaz LA Jr;Hartigan J;Smith DR;Strausberg RL;Marie SK;Shinjo SM;Yan H;Riggins GJ;Bigner DD;Karchin R;Papadopoulos N;Parmigiani G;Vogelstein B;Velculescu VE;Kinzler KW
通讯作者：
Kinzler KW