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

被引：0
作者：
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
机构：
[1] Cell Signaling and Cancer Laboratory,Department of Medicine
[2] Institute of Hepatology,Division of Gastrointestinal and Liver Pathology
[3] Foundation for Liver Research,Department of Medical Oncology
[4] Section of Inflammation and Signal Transduction,Department of Medicine
[5] Imperial College,undefined
[6] The Sol Goldman Pancreatic Cancer Research Center,undefined
[7] The Johns Hopkins University School of Medicine,undefined
[8] Henan Cancer Hospital,undefined
[9] Section of Molecular Immunology,undefined
[10] Imperial College,undefined
[11] Institute of Organic Synthesis and Photoreactivity,undefined
[12] National Research Council,undefined
[13] Cancer Research UK Cambridge Research Institute,undefined
[14] Li Ka Shing Centre,undefined
[15] Viral Hepatitis Laboratory,undefined
[16] Institute of Hepatology,undefined
[17] Foundation for Liver Research,undefined
[18] Present address: Department of Life Sciences,undefined
[19] Division of Biosciences,undefined
[20] College of Health and Life Sciences,undefined
[21] Brunel University London,undefined
[22] Uxbridge UB8 3PH,undefined
[23] UK.,undefined
来源：
Nature Communications | / 6卷
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摘要：
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.
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[1]  
Vander Heiden MG(2009)Understanding the Warburg effect: the metabolic requirements of cell proliferation Science 324 1029-1033
[2]  
Cantley LC(2011)Regulation of cancer cell metabolism Nat. Rev. Cancer 11 85-95
[3]  
Thompson CB(2008)Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c Nat. Cell Biol. 10 1477-1483
[4]  
Cairns RA(2009)Tumor suppressors and cell metabolism: a recipe for cancer growth Genes Dev. 23 537-548
[5]  
Harris IS(2011)Proliferative activity in hepatocellular carcinoma is closely correlated with glucose metabolism but not angiogenesis J. Hepatol. 55 846-857
[6]  
Mak TW(2013)Tissue metabolomics of hepatocellular carcinoma: tumor energy metabolism and the role of transcriptomic classification Hepatology 58 229-238
[7]  
Vaughn AE(2013)The metabolomic window into hepatobiliary disease J Hepatol. 59 842-858
[8]  
Deshmukh M(2004)Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4 891-899
[9]  
Jones RG(2006)TIGAR, a p53-inducible regulator of glycolysis and apoptosis Cell 126 107-120
[10]  
Thompson CB(1997)c-Myc transactivation of LDH-A: implications for tumor metabolism and growth Proc. Natl Acad. Sci. USA 94 6658-6663
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