TY - JOUR
T1 - Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells
AU - Yun, Jihye
AU - Rago, Carlo
AU - Cheong, Ian
AU - Pagliarini, Ray
AU - Angenendt, Philipp
AU - Rajagopalan, Harith
AU - Schmidt, Kerstin
AU - Willson, James K V
AU - Markowitz, Sandy
AU - Zhou, Shibin
AU - Diaz, Luis A.
AU - Velculescu, Victor E.
AU - Lengauer, Christoph
AU - Kinzler, Kenneth W.
AU - Vogelstein, Bert
AU - Papadopoulos, Nickolas
PY - 2009
Y1 - 2009
N2 - 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 up-regulated 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 KRAS mutations not present in their parents. 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.
AB - 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 up-regulated 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 KRAS mutations not present in their parents. 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.
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U2 - 10.1126/science.1174229
DO - 10.1126/science.1174229
M3 - Article
C2 - 19661383
AN - SCOPUS:70349331678
SN - 0036-8075
VL - 325
SP - 1555
EP - 1559
JO - Science
JF - Science
IS - 5947
ER -