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.

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Acknowledgements

This work was supported in part by NIH grants CA140515, CA183594, CA174786 (J.C.), CA175316 (S.K.), GM071440 (C.H.) and the Pharmacological Sciences Training Grant T32 GM008602 (S.E.), DoD grant W81XWH-12-1-0217 (J.C.), National Natural Science Funds of China No. 20902013 (L.Zhou), Charles Harris Run For Leukemia, Inc. (H.J.K.) and the Hematology Tissue Bank of the Emory University School of Medicine and the Georgia Cancer Coalition (H.J.K.). T.H. is a Fellow Scholar of the American Society of Hematology. S.E. is a NIH pre-doctoral fellow and an ARCS Foundation Scholar. H.J.K., F.R.K., S.K. and J.C. are Georgia Cancer Coalition Distinguished Cancer Scholars. S.K. is a Robbins Scholar. S.K. and J.C. are American Cancer Society Basic Research Scholars. J.C. is a Scholar of the Leukemia and Lymphoma Society.

Author information

Author notes

    • Ruiting Lin
    • , Shannon Elf
    •  & Changliang Shan

    These authors contributed equally to this work.

Affiliations

  1. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA

    • Ruiting Lin
    • , Shannon Elf
    • , Changliang Shan
    • , Hee-Bum Kang
    • , Taro Hitosugi
    • , Jae Ho Seo
    • , Dongsheng Wang
    • , Georgia Zhuo Chen
    • , Sagar Lonial
    • , Martha L. Arellano
    • , Hanna J. Khoury
    • , Fadlo R. Khuri
    • , Sumin Kang
    • , Jun Fan
    •  & Jing Chen
  2. Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA

    • Quanjiang Ji
    • , Lu Zhou
    • , Liang Zhang
    •  & Chuan He
  3. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA

    • Shuai Zhang
    • , Daniel J. Brat
    •  & Keqiang Ye
  4. Cell Signaling Technology, Inc. (CST), Danvers, Massachusetts 01923, USA

    • Jianxin Xie
    • , Meghan Tucker
    •  & Ting-Lei Gu
  5. Children’s Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA

    • Jessica Sudderth
    • , Lei Jiang
    •  & Ralph J. DeBerardinis
  6. Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas 75390, USA

    • Matthew Mitsche
  7. Department of Chemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA

    • Shaoxiong Wu
  8. Department of Radiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA

    • Yuancheng Li
    •  & Hui Mao
  9. College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China

    • Peng R. Chen
  10. Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA

    • Selwyn J. Hurwitz
  11. Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA

    • Benjamin H. Lee
  12. School of Basic Medical Sciences, Fudan University, Shanghai 200032, China

    • Qunying Lei
  13. Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Titus J. Boggon

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Contributions

R.L., S.E. and C.S. contributed equally to this work. J.X., T.-L.G., S.Z., K.Y., P.R.C., D.J.B., M.L.A., S.L., H.J.K., Q.L. and F.R.K. provided critical reagents. S.J.H. performed data analysis of pharmacokinetics studies. M.T. and T.-L.G. performed mass spectrometry-based assays. Q.J., L.Zhou, L.Zhang and C.H. performed biochemical analysis of lysine-acetylated 6PGD and molecular docking studies and analysed the data. J.S., L.J., M.M., R.J.D., S.W., Y.L. and H.M. performed quantitative mass spectrometry and NMR-based assays, and analysed data. B.H.L. performed the histopathological analyses. T.J.B. performed structural analyses. D.W. and G.Z.C. helped with xenograft experiments. C.S., S.E., H.-B.K., J.H.S., T.H. and J.F. performed all other experiments. R.L., S.E., C.S., S.K., J.F. and J.C. designed the study and wrote the paper. S.K., J.F. and J.C. are senior authors and jointly managed the project. All authors read and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sumin Kang or Jun Fan or Jing Chen.

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https://doi.org/10.1038/ncb3255

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