title: 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling.
abstract: The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.lastname: Elf
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Changliang
authors.identifier: http://orcid.org/0000-0002-4906-1686
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authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Quanjiang
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authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Lu
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authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.lastname: Hitosugi
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Liang
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authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Shuai
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authors.lastname: Zhang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Jae Ho
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authors.affiliation: Cell Signaling Technology, Inc. (CST), Danvers, Massachusetts 01923, USA.
authors.forename: Jianxin
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authors.affiliation: Cell Signaling Technology, Inc. (CST), Danvers, Massachusetts 01923, USA.
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authors.affiliation: Cell Signaling Technology, Inc. (CST), Danvers, Massachusetts 01923, USA.
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authors.affiliation: Children's Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Jessica
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authors.affiliation: Children's Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
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authors.affiliation: Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
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authors.affiliation: Children's Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Ralph J
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authors.lastname: DeBerardinis
authors.affiliation: Department of Chemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Department of Radiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Yuancheng
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authors.affiliation: Department of Radiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Hui
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authors.affiliation: College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
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authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Benjamin H
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authors.affiliation: School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Qunying
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authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Titus J
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authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA.
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authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D006801:Humans; D050155:Lipogenesis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010427:Pentose Phosphate Pathway; D010734:Phosphogluconate Dehydrogenase / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012274:Ribulosephosphates / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D012274:Ribulosephosphates; C031524:ribulose 5-phosphate; D010734:Phosphogluconate Dehydrogenase; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases