Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells.
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.
Yun
Jihye
J
Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
Rago
Carlo
C
Cheong
Ian
I
Pagliarini
Ray
R
Angenendt
Philipp
P
Rajagopalan
Harith
H
Schmidt
Kerstin
K
Willson
James K V
JK
Markowitz
Sandy
S
Zhou
Shibin
S
Diaz
Luis A
LA
Velculescu
Victor E
VE
Lengauer
Christoph
C
Kinzler
Kenneth W
KW
Vogelstein
Bert
B
Papadopoulos
Nickolas
N
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D011905:Genes, ras; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011773:Pyruvates / Q000494:pharmacology; D014183:Transplantation, Heterologous
D051272:Glucose Transporter Type 1; D011773:Pyruvates; C495677:SLC2A1 protein, human; D019344:Lactic Acid; C017092:bromopyruvate; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D005947:Glucose