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 and Salvatore Papa ()
Additional contact information
Valeria Iansante: Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research
Pui Man Choy: Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research
Sze Wai Fung: Section of Inflammation and Signal Transduction, Imperial College
Ying Liu: The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
Jian-Guo Chai: Section of Molecular Immunology, Imperial College
Julian Dyson: Section of Molecular Immunology, Imperial College
Alberto Del Rio: Institute of Organic Synthesis and Photoreactivity, National Research Council
Clive D’Santos: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre
Roger Williams: Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research
Shilpa Chokshi: Viral Hepatitis Laboratory, Institute of Hepatology, Foundation for Liver Research
Robert A Anders: The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
Concetta Bubici: Section of Inflammation and Signal Transduction, Imperial College
Salvatore Papa: Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8882

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