Oncogenic KRAS Drives Metabolic Vulnerabilities by Directly Regulating Metabolic Enzymes in Cancer

Abstract

Metabolic reprogramming, such as enhanced aerobic glycolysis, allows cancer cells to maintain viability and promote proliferation. It is one of the major consequences of oncogenic mutations. KRAS is the most frequently mutated oncogene in human cancer. It is thought to be closely related to metabolic reprogramming. However, it is not clear whether it can participate in metabolic reprogramming by directly regulating metabolic enzymes. Additionally, the functional differences among the splice variants of KRAS have not been determined. In a study, recently published in Nature, Amendola et al reported a unique interaction between one of the KRAS splice variants (KRAS4A) and the major glycolytic enzyme (hexokinase 1) in cancer cells. Their findings indicated that a better understanding on the regulation of hexokinase 1 by KRAS may reveal novel therapeutic strategies.

Keywords

cancer metabolism - metabolic reprogramming - aerobic glycolysis - KRAS - KRAS4A hexokinase 1

Author's Contribution

The author read and approved the final manuscript.

• References

• 1 Wang Y, Xia Y, Lu Z. Metabolic features of cancer cells. Cancer Commun (Lond) 2018; 38 (01) 65
• 2 Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab 2016; 23 (01) 27-47
• 3 Sciacovelli M, Frezza C. Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer. FEBS J 2017; 284 (19) 3132-3144
• 4 Kuo CY, Ann DK. When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance. Cancer Commun 2018; 38 (01) 47
• 5 Luengo A, Gui DY, Vander Heiden MG. Targeting Metabolism for Cancer Therapy. Cell Chem Biol 2017; 24 (09) 1161-1180
• 6 Cheng C, Geng F, Cheng X, Guo D. Lipid metabolism reprogramming and its potential targets in cancer. Cancer Commun 2018; 38 (01) 27
• 7 Dang CV. Links between metabolism and cancer. Genes Dev 2012; 26 (09) 877-890
• 8 Lu S, Wang Y. Nonmetabolic functions of metabolic enzymes in cancer development. Cancer Commun 2018; 38 (01) 63
• 9 Ying H, Kimmelman AC, Lyssiotis CA. , et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 2012; 149 (03) 656-670
• 10 Kimmelman AC. Metabolic dependencies in RAS-driven cancers. Clin Cancer Res 2015; 21 (08) 1828-1834
• 11 Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature 2016; 531 (7592): 110-113
• 12 Tsai FD, Lopes MS, Zhou M. , et al. K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif. Proc Natl Acad Sci U S A 2015; 112 (03) 779-784
• 13 Voice JK, Klemke RL, Le A, Jackson JH. Four human ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility. J Biol Chem 1999; 274 (24) 17164-17170
• 14 Amendola CR, Mahaffey JP, Parker SJ. , et al. KRAS4A directly regulates hexokinase 1. Nature 2019; 576 (7787): 482-486
• 15 Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 2001; 15 (11) 1406-1418
• 16 Vyssokikh MY, Brdiczka D. The function of complexes between the outer mitochondrial membrane pore (VDAC) and the adenine nucleotide translocase in regulation of energy metabolism and apoptosis. Acta Biochim Pol 2003; 50 (02) 389-404