Revving the engine: PKB/AKT as a key regulator of cellular glucose metabolism

Abstract

Glucose metabolism is of critical importance for cell growth and proliferation, the disorders of which have been widely implicated in cancer progression. Glucose uptake is achieved differently by normal cells and cancer cells. Even in an aerobic environment, cancer cells tend to undergo metabolism through glycolysis rather than the oxidative phosphorylation pathway. Disordered metabolic syndrome is characterized by elevated levels of metabolites that can cause changes in the tumor microenvironment, thereby promoting tumor recurrence and metastasis. The activation of glycolysis-related proteins and transcription factors is involved in the regulation of cellular glucose metabolism. Changes in glucose metabolism activity are closely related to activation of protein kinase B (PKB/AKT). This review discusses recent findings on the regulation of glucose metabolism by AKT in tumors. Furthermore, the review summarizes the potential importance of AKT in the regulation of each process throughout glucose metabolism to provide a theoretical basis for AKT as a target for cancers.

Keywords: AKT; cancer; glucose glycolysis; glucose uptake; tricarboxylic acid cycle.

FIGURE 1

AKT can be modified through post-translational modifications (PTMs) including ubiquitination and methylation. The ubiquitination of AKT significantly regulates the activity of the mTORC1, AMPK and PTEN signaling. In addition, the CHIP, MULAN, Lysine Demethylase 4B (KDM4B) and TTC3 can ubiquitinate AKT and mediate its degradation. Furthermore, protein arginine methyltransferases 5(PRMT5) directly methylates AKT1-R391 to promote AKT activity. In addition, SETDB1-mediated methylation of AKT1 which promotes cell growth and glycolysis.

FIGURE 2

AKT regulates glucose uptake. AKT regulates the transcription of GLUTs by HIF-1α and NF-κB. Conversely AKT can directly phosphorylate targets (AS160, TBC1D1, PIKfyve, TXNIP) to regulate GLUTs trafficking.

FIGURE 3

AKT regulates glycolysis and the tricarboxylic acid cycle. AKT regulates the transcription of glycolysis enzymes by FoxOs, c-Myc, and HIF-1α. However, AKT can directly phosphorylate the glycolytic enzymes HK, PFK1, GAPDH, PGK, and PK. HK: Hexokinase; GPI: Glucose 6-phosphate isomerase; PFK1 phosphofructokinase 1; TPI triose phosphate isomerase; GAPDH, Glyceraldehyde 3-phosphate dehydrogenase; PGK: phosphoglycerate kinase; PGM: Phosphoglycerate mutase; PK: Pyruvate kinase. AKT can inhibit the influx of acetyl-CoA into the TCA cycle by inhibiting PDH-E1αactivity. Furthermore, AKT can promote the conversion of glutamine into α-ketoglutarate to compensate for the depletion of the intermediates of the TCA cycle. GLS: Glutaminase, α-KG: α-ketoglutarate.