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Nat Cell Biol. 2015 Nov;17(11):1484-96. doi: 10.1038/ncb3255. Epub 2015 Oct 19.

6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling.

Author information

  • 1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
  • 2Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA.
  • 3Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
  • 4Cell Signaling Technology, Inc. (CST), Danvers, Massachusetts 01923, USA.
  • 5Children's Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 6Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 7Department of Chemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
  • 8Department of Radiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
  • 9College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
  • 10Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
  • 11Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
  • 12School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 13Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

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.

PMID:
26479318
PMCID:
PMC4628560
DOI:
10.1038/ncb3255
[PubMed - indexed for MEDLINE]
Free PMC Article
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