Editors' ChoiceCancer

Kras rewires metabolic networks

Sci. Signal.  08 Mar 2016:
Vol. 9, Issue 418, pp. ec56
DOI: 10.1126/scisignal.aaf6232

Mutations in Kras are associated with lung tumor formation. Tumor progression is enabled by positive selection of Kras homozygous mutations over heterozygous mutations. Kerr et al. investigated the gain-of-function phenotypic differences in mouse embryonic fibroblasts (MEFs) that were Kraswild-type/wild-type (WT/WT), KrasG12D/WT (heterozygous), and KrasG12D/G12D (homozygous), and in human heterozygous and homozygous non–small cell lung cancer (NSCLC). Because the KrasG12D/WT and KrasG12D/G12D MEFs had similar growth rates for the first five passages of the cell lines, the authors characterized and compared the phenotypic alterations in the KrasG12D/WT and KrasG12D/G12D MEFs before the sixth passage of the cell lines. Aside from a twofold increase in Ras abundance in KrasG12D/G12D cells, there were no differences in overall protein abundances in KrasG12D/WT and KrasG12D/G12D MEFs. Microarray analysis showed that the expression of genes associated with glycolysis was significantly higher in the KrasG12D/G12D cells than in KrasG12D/WT cells. Glucose consumption and lactate secretion were increased in KrasG12D/G12D cells compared with KrasG12D/WT cells and in Kras mutant homozygous NSCLCs compared with heterozygous NSCLCs. Liquid chromatography–mass spectrometry (LC-MS)–based metabolomics analysis revealed significant increases in tricarboxylic acid (TCA) cycle intermediates in KrasG12D/G12D MEFs and Kras mutant homozygous NSCLCs relative to their respective heterozygous controls. Metabolomics analysis also revealed that more carbons were derived from glucose in glutathione (GSH) and its precursors serine, glycine, and glutamate in cancer cells with homozygous mutations. This finding suggested that cells with Kras mutations shunted glucose towards glutathione biosynthesis. In addition, KrasG12D/G12D cells showed increased NADPH and GSH synthesis and NADPH/NADP+ and GSH/GSSG ratios compared with KrasG12D/WT cells, suggesting increased resistance to damage induced by reactive oxygen species (ROS). Growth of KrasG12D/G12D cells in low glucose medium increased apoptosis and growth of these cells in medium with the glucose analogue 2-deoxy-D-glucose (2DG) increased ROS. Exposure of KrasG12D/G12D MEFs and human Kras mutant homozygous NSCLCs to both 2DG and a GSH biosynthesis inhibitor increased apoptosis compared with their respective controls. Metabolomic analysis of lung tumors that generated spontaneously in KrasG12D/+ mice revealed enrichment of glucose-derived TCA metabolites, serine, glycine, and GSH during tumor progression. Therefore, this study suggests an association between the increased malignancies in Kras mutant cancer cells and metabolic alterations.

E. M. Kerr, E. Gaude, F. K. Turrell, C. Frezza, C. P. Martins, Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature, 531, 110–113 (2016). [PubMed]

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