PIM2 phosphorylates PKM2 and promotes Glycolysis in Cancer Cells.

Shanghai Jiao Tong University, China
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2013; DOI: 10.1074/jbc.M113.508226
Source: PubMed


Pyruvate kinase M2 (PKM2) is a key player in the Warburg effect of cancer cells. However, the mechanisms of regulating PKM2
are not fully elucidated. Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding
partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting
in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed
a reduced effect on glycolysis, co-activating HIF-1α and β-catenin, and cell proliferation, while enhancing mitochondrial
respiration of cancer cells. These findings demonstrate that PIM2-dependent phosphorylation of PKM2 is critical for regulating
the Warburg effect in cancer, highlighting PIM2 as a potential therapeutic target.

Download full-text


Available from: Lei Xie

Click to see the full-text of:

Article: PIM2 phosphorylates PKM2 and promotes Glycolysis in Cancer Cells.

2.38 MB

See full-text
  • [Show abstract] [Hide abstract]
    ABSTRACT: Reprogramming of cell metabolism is essential for tumorigenesis, and is regulated by a complex network, in which PKM2 plays a critical role. PKM2 exists as an inactive monomer, less active dimer and active tetramer. While dimeric PKM2 diverts glucose metabolism towards anabolism through aerobic glycolysis, tetrameric PKM2 promotes the flux of glucose-derived carbons for ATP production via oxidative phosphorylation. Equilibrium of the PKM2 dimers and tetramers is critical for tumorigenesis, and is controlled by multiple factors. The PKM2 dimer also promotes aerobic glycolysis by modulating transcriptional regulation. We will discuss the current understanding of PKM2 in regulating cancer metabolism.
    No preview · Article · Feb 2014 · Cancer letters
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To survive under hypoxic conditions, cancer cells remodel glucose metabolism to support tumor progression. HIF transcription factor is essential for cellular response to hypoxia. The underlying mechanism how HIF is constitutively activated in cancer cells remains elusive. In the present study, we characterized a regulatory feedback loop between HIF-1α and PIM2 in HepG2 cells. Serine/threonine kinase proto-oncogene PIM2 level was induced upon hypoxia in a HIF-1α-mediated manner in cancer cells. HIF-1α induced PIM2 expression via binding to the hypoxia-responsive elements (HREs) of the PIM2 promoter. In turn, PIM2 interacted with HIF-1α, especially a transactivation domain of HIF-1α. PIM2 as a co-factor but not an upstream kinase of HIF-1α, enhanced HIF-1α effect in response to hypoxia. The positive feedback loop between PIM2 and HIF-1α was correlated with glucose metabolism as well as cell survival in HepG2 cells. Such a regulatory mode may be important for the adaptive responses of cancer cells in antagonizing hypoxia during cancer progression.
    Full-text · Article · Feb 2014 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pyruvate kinase M2 (PKM2) is predominantly expressed in cancers, which is considered as a key regulator of the Warburg effect. In this study, HSP40 was identified as a novel binding partner of PKM2. HSP40-PKM2 association destabilized PKM2 protein through HSC70. In the presence of HSP40, PKM2 protein level and PKM2-mediated PDK1 expression were down-regulated. Moreover, HSP40 was involved in regulating glucose metabolism on PKM2 dependent way and at the mean time had an effect on mitochondrial oxygen respiration. In line with inhibition effect of HSP40 on glycolysis, the growth of cancer cells was inhibited by HSP40.Our data provided a new regulation mechanism of PKM2, which suggested a new therapeutic target for cancer therapy.
    Full-text · Article · Mar 2014 · PLoS ONE
Show more