2. Academic Validation
  3. 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling

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

  • Nat Cell Biol. 2015 Nov;17(11):1484-96. doi: 10.1038/ncb3255.
Ruiting Lin 1,  Shannon Elf 1,  Changliang Shan 1,  Hee-Bum Kang 1,  Quanjiang Ji 2,  Lu Zhou 2,  Taro Hitosugi 1,  Liang Zhang 2,  Shuai Zhang 3,  Jae Ho Seo 1,  Jianxin Xie 4,  Meghan Tucker 4,  Ting-Lei Gu 4,  Jessica Sudderth 5,  Lei Jiang 5,  Matthew Mitsche 6,  Ralph J DeBerardinis 5,  Shaoxiong Wu 7,  Yuancheng Li 8,  Hui Mao 8,  Peng R Chen 9,  Dongsheng Wang 1,  Georgia Zhuo Chen 1,  Selwyn J Hurwitz 10,  Sagar Lonial 1,  Martha L Arellano 1,  Hanna J Khoury 1,  Fadlo R Khuri 1,  Benjamin H Lee 11,  Qunying Lei 12,  Daniel J Brat 3,  Keqiang Ye 3,  Titus J Boggon 13,  Chuan He 2,  Sumin Kang 1,  Jun Fan 1,  Jing Chen 1
Affiliations

Affiliations

  • 1 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
  • 2 Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA.
  • 3 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
  • 4 Cell Signaling Technology, Inc. (CST), Danvers, Massachusetts 01923, USA.
  • 5 Children's Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 6 Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 7 Department of Chemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
  • 8 Department of Radiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
  • 9 College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
  • 10 Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
  • 11 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
  • 12 School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 13 Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
PMID: 26479318 DOI: 10.1038/ncb3255
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.

Figures
Products