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

Valeria Iansante, Pui Man Choy, Sze Wai Fung, Ying Liu, Jian Guo Chai, Julian Dyson, Alberto Del Rio, Clive D'Santos, Roger Williams, Shilpa Chokshi, Robert A Anders, Concetta Bubici, Salvatore Papa

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number8882
JournalNature Communications
Volume6
DOIs
StatePublished - Aug 10 2015

Fingerprint

pyruvates
phosphorylation
Phosphorylation
Pyruvate Kinase
Tumors
Hepatocellular Carcinoma
Protein Isoforms
apoptosis
cancer
Chemical activation
Mitogen-Activated Protein Kinase 8
glycolysis
activation
Apoptosis
tumors
Glycolysis
Cells
Apoptosis Regulatory Proteins
Poly(ADP-ribose) Polymerases
ribose

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation. / Iansante, Valeria; Choy, Pui Man; Fung, Sze Wai; Liu, Ying; Chai, Jian Guo; Dyson, Julian; Del Rio, Alberto; D'Santos, Clive; Williams, Roger; Chokshi, Shilpa; Anders, Robert A; Bubici, Concetta; Papa, Salvatore.

In: Nature Communications, Vol. 6, 8882, 10.08.2015.

Research output: Contribution to journalArticle

Iansante, V, Choy, PM, Fung, SW, Liu, Y, Chai, JG, Dyson, J, Del Rio, A, D'Santos, C, Williams, R, Chokshi, S, Anders, RA, Bubici, C & Papa, S 2015, 'PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation', Nature Communications, vol. 6, 8882. https://doi.org/10.1038/ncomms8882
Iansante, Valeria ; Choy, Pui Man ; Fung, Sze Wai ; Liu, Ying ; Chai, Jian Guo ; Dyson, Julian ; Del Rio, Alberto ; D'Santos, Clive ; Williams, Roger ; Chokshi, Shilpa ; Anders, Robert A ; Bubici, Concetta ; Papa, Salvatore. / PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation. In: Nature Communications. 2015 ; Vol. 6.
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