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

Liyi Zhang

doi:10.1055/s-0040-1712456

Global Medical Genetics, Inhaltsverzeichnis

CC BY 4.0 · Glob Med Genet 2020; 07(01): 001-002
DOI: 10.1055/s-0040-1712456

Rapid Communication

Georg Thieme Verlag KG Stuttgart · New York

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

Liyi Zhang

¹State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China

› Institutsangaben

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

Volltext

Referenzen

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