PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation

Nat Commun. 2015 Aug 10;6:7882. doi: 10.1038/ncomms8882.

Abstract

Most tumour cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and evade apoptosis. Intriguingly, the molecular mechanisms that link the Warburg effect with the suppression of apoptosis are not well understood. In this study, using loss-of-function studies in vitro and in vivo, we show that the anti-apoptotic protein poly(ADP-ribose) polymerase (PARP)14 promotes aerobic glycolysis in human hepatocellular carcinoma (HCC) by maintaining low activity of the pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. Notably, PARP14 is highly expressed in HCC primary tumours and associated with poor patient prognosis. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365. Moreover, targeting PARP14 enhances the sensitization of HCC cells to anti-HCC agents. Our findings indicate that the PARP14-JNK1-PKM2 regulatory axis is an important determinant for the Warburg effect in tumour cells and provide a mechanistic link between apoptosis and metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Carcinoma, Hepatocellular / metabolism*
  • Carrier Proteins / metabolism*
  • Gene Knockdown Techniques
  • Glycolysis
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Liver Cirrhosis / metabolism
  • Liver Neoplasms / metabolism*
  • MCF-7 Cells
  • Membrane Proteins / metabolism*
  • Mitogen-Activated Protein Kinase 8 / metabolism*
  • Phosphorylation
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Thyroid Hormones / metabolism*
  • Up-Regulation

Substances

  • Carrier Proteins
  • Membrane Proteins
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • PARP14 protein, human
  • Poly(ADP-ribose) Polymerases
  • Mitogen-Activated Protein Kinase 8