Regulation and function of pyruvate kinase M2 in cancer

Abstract

Altered metabolism is fundamental to the growth and survival of cancer cells. Pyruvate kinase M2 (PKM2), a key enzyme in cancer metabolism, has been demonstrated to play a central role not only in metabolic reprogramming but also in direct regulation of gene expression and subsequent cell cycle progression. This review outlines the current understanding of PKM2 protein kinase activity and regulatory mechanisms underlying PKM2 expression, enzymatic activity, and nuclear localization, thus highlighting PKM2 as a potential therapeutic target.

Keywords: Gene expression; PKM2; The Warburg effect.

Conflict of interest statement

Conflict of Interest Statement

None

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Figures

Fig.1

Regulation of PKM transcription. (A) PKM promoter activity is activated by transcription factor SP1 and inhibited by SP3. (B) PKM2 hydroxylated by PHD3 interacts directly with HIF1, which increases transcriptional activity of HIF1 and promotes recruitments of p300 to the PKM promoter. (C) Monoubiquitylated PKC interacts with NEMO and recruits the IKK complex, leading to phosphorylation of IKK. IKK -activated RelA/p50, which is associated with HIF1, binds to the PKM promoter and initiates the transcription of PKM2.

Fig.2

Regulation of glycolytic activity of PKM2. PKM2 glycolytic activity can be regulated by not only metabolic intermediates, but also post-translational modification of PKM2 induced by different stimuli.

Fig.3

A model of EGF-induced nuclear translocation of PKM2 and PKM2-promoted Warburg effect. Upon EGF receptor activation, PKM2 is phosphorylated by ERK2 at S37. PIN1 binds to and isomerizes phosphorylated PKM2, resulting in the recruitment of importin 5 and translocation of PKM2 into the nucleus. Nuclear PKM2 binds to -catenin and enhances c-Myc expression, which subsequently increases the expression of GLUT1, LDHA, PTB and PKM2 itself, thereby promoting the Warburg effect and tumorigenesis.