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

Title: PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation
Author(s): Iansante, V
Choy, PM
Fung, SW
Liu, Y
Chai, J-G
Dyson, J
Del Rio, A
D'Santos, C
Williams, R
Chokshi, S
Anders, RA
Bubici, C
Papa, S
Item Type: Journal Article
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 Date: 10-Aug-2015
Date of Acceptance: 23-Jun-2015
URI: http://hdl.handle.net/10044/1/41780
DOI: http://dx.doi.org/10.1038/ncomms8882
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 6
Copyright Statement: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
PYRUVATE-KINASE M2
TUMOR-GROWTH
GLUCOSE-METABOLISM
ENERGY-METABOLISM
CELL-METABOLISM
POOR-PROGNOSIS
CYTOCHROME-C
CANCER-CELLS
APOPTOSIS
GLYCOLYSIS
Apoptosis
Carcinoma, Hepatocellular
Carrier Proteins
Gene Knockdown Techniques
Glycolysis
HEK293 Cells
Hep G2 Cells
Humans
Liver Cirrhosis
Liver Neoplasms
MCF-7 Cells
Membrane Proteins
Mitogen-Activated Protein Kinase 8
Phosphorylation
Poly(ADP-ribose) Polymerases
Thyroid Hormones
Up-Regulation
Humans
Carcinoma, Hepatocellular
Liver Neoplasms
Liver Cirrhosis
Thyroid Hormones
Poly(ADP-ribose) Polymerases
Mitogen-Activated Protein Kinase 8
Carrier Proteins
Membrane Proteins
Apoptosis
Up-Regulation
Glycolysis
Phosphorylation
Gene Knockdown Techniques
Hep G2 Cells
HEK293 Cells
MCF-7 Cells
MD Multidisciplinary
Publication Status: Published
Article Number: 7882
Appears in Collections:Division of Surgery
Department of Medicine



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