title: Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells.
abstract: 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.
authors: Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
authors: Jihye
authors: J
authors: Yun
authors: Carlo
authors: C
authors: Rago
authors: Ian
authors: I
authors: Cheong
authors: Ray
authors: R
authors: Pagliarini
authors: Philipp
authors: P
authors: Angenendt
authors: Harith
authors: H
authors: Rajagopalan
authors: Kerstin
authors: K
authors: Schmidt
authors: James K V
authors: JK
authors: Willson
authors: Sandy
authors: S
authors: Markowitz
authors: Shibin
authors: S
authors: Zhou
authors: Luis A
authors: LA
authors: Diaz
authors: Victor E
authors: VE
authors: Velculescu
authors: Christoph
authors: C
authors: Lengauer
authors: Kenneth W
authors: KW
authors: Kinzler
authors: Bert
authors: B
authors: Vogelstein
authors: Nickolas
authors: N
authors: Papadopoulos
mesh_terms: 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
chemical_list: 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