The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid β-oxidation
- 4 April 2005
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 24 (26), 4165-4173
- https://doi.org/10.1038/sj.onc.1208622
Abstract
Activation of the oncogenic kinase Akt stimulates glucose uptake and metabolism in cancer cells and renders these cells susceptible to death in response to glucose withdrawal. Here we show that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reverses the sensitivity of Akt-expressing glioblastoma cells to glucose deprivation. AICAR's protection depends on the activation of AMPK, as expression of a dominant-negative form of AMPK abolished this effect. AMPK is a cellular energy sensor whose activation can both block anabolic pathways such as protein synthesis and activate catabolic reactions such as fatty acid oxidation to maintain cellular bioenergetics. While rapamycin treatment mimicked the effect of AICAR on inhibiting markers of cap-dependent translation, it failed to protect Akt-expressing cells from death upon glucose withdrawal. Compared to control cells, Akt-expressing cells were impaired in the ability to induce fatty acid oxidation in response to glucose deprivation unless stimulated with AICAR. Stimulation of fatty acid oxidation was sufficient to maintain cell survival as activation of fatty acid oxidation with bezafibrate also protected Akt-expressing cells from glucose withdrawal-induced death. Conversely, treatment with a CPT-1 inhibitor to block fatty acid import into mitochondria prevented AICAR from stimulating fatty acid oxidation and promoting cell survival in the absence of glucose. Finally, cell survival did not require reversal of Akt's effects on either protein translation or lipid synthesis as the addition of the cell penetrant oxidizable substrate methyl-pyruvate was sufficient to maintain survival of Akt-expressing cells deprived of glucose. Together, these data suggest that activation of Akt blocks the ability of cancer cells to metabolize nonglycolytic bioenergetic substrates, leading to glucose addiction.This publication has 29 references indexed in Scilit:
- Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetesNature, 2004
- Akt Stimulates Aerobic Glycolysis in Cancer CellsCancer Research, 2004
- BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosisNature, 2003
- Critical roles of AMP-activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formationOncogene, 2002
- The Identification of ATP-citrate Lyase as a Protein Kinase B (Akt) Substrate in Primary AdipocytesPublished by Elsevier BV ,2002
- AMP-activated Protein Kinase Suppresses Protein Synthesis in Rat Skeletal Muscle through Down-regulated Mammalian Target of Rapamycin (mTOR) SignalingPublished by Elsevier BV ,2002
- 5-Amino-4-imidazolecarboxamide Riboside Confers Strong Tolerance to Glucose Starvation in a 5′-AMP-Activated Protein Kinase-Dependent FashionBiochemical and Biophysical Research Communications, 2002
- Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinaseGenes & Development, 2001
- 5-Aminoimidazole-4-Carboxamide Ribonucleoside. A Specific Method for Activating AMP-Activated Protein Kinase in Intact Cells?JBIC Journal of Biological Inorganic Chemistry, 1995
- Location and function of three sites phosphorylated on rat acetyl‐CoA carboxylase by the AMP‐activated protein kinaseEuropean Journal of Biochemistry, 1990