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

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

Author information

1
Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, UK.
2
Department of Medicine, Section of Inflammation and Signal Transduction, Imperial College, London W12 0NN, UK.
3
1] The Sol Goldman Pancreatic Cancer Research Center, Division of Gastrointestinal and Liver Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA [2] Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou, Henan 450000, China.
4
Department of Medicine, Section of Molecular Immunology, Imperial College, London W12 0NN, UK.
5
Institute of Organic Synthesis and Photoreactivity, National Research Council, Bologna 40129, Italy.
6
Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
7
1] Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, UK [2] Viral Hepatitis Laboratory, Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, UK.
8
Viral Hepatitis Laboratory, Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, UK.
9
The Sol Goldman Pancreatic Cancer Research Center, Division of Gastrointestinal and Liver Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.

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.

PMID:
26258887
PMCID:
PMC4918319
DOI:
10.1038/ncomms8882
[Indexed for MEDLINE]
Free PMC Article

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