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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  1. 1.

    On the origin of cancer cells. Science 123, 309–314 (1956).

  2. 2.

    , & Regulation of cancer cell metabolism. Nat. Rev. Cancer 11, 85–95 (2011).

  3. 3.

    & Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13, 472–482 (2008).

  4. 4.

    et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).

  5. 5.

    et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell 22, 585–600 (2012).

  6. 6.

    et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat. Genet. 43, 869–874 (2011).

  7. 7.

    et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011).

  8. 8.

    et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329, 1492–1499 (2010).

  9. 9.

    et al. Importance of glucose-6-phosphate dehydrogenase activity for cell growth. J. Biol. Chem. 273, 10609–10617 (1998).

  10. 10.

    , & Mitogenic action of insulin-like growth factor-I on human osteosarcoma MG-63 cells and rat osteoblasts maintained in situ: the role of glucose-6-phosphate dehydrogenase. Bone Miner. 22, 105–115 (1993).

  11. 11.

    et al. Importance of glucose-6-phosphate dehydrogenase activity in cell death. Am. J. Physiol. 276, C1121–C1131 (1999).

  12. 12.

    et al. A new G6PD knockdown tumor-cell line with reduced proliferation and increased susceptibility to oxidative stress. Cancer Biother. Radiopharm. 24, 81–90 (2009).

  13. 13.

    et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).

  14. 14.

    et al. 6-Aminonicotinamide sensitizes human tumor cell lines to cisplatin. Clin. Cancer Res. 4, 117–130 (1998).

  15. 15.

    , , , & Relationships between UMPK and PGD activities and deletions of chromosome 1p in colorectal cancers. Cancer Genet. Cytogenet. 56, 45–56 (1991).

  16. 16.

    et al. Increased activity of 6-phosphogluconate dehydrogenase and glucose-6-phosphate dehydrogenase in purified cell suspensions and single cells from the uterine cervix in cervical intraepithelial neoplasia. Br. J. Cancer 66, 185–191 (1992).

  17. 17.

    et al. Alterations in erythrocyte glutathione metabolism associated with cervical dysplasias and carcinoma in situ. Cancer Invest. 11, 652–659 (1993).

  18. 18.

    et al. Fine-needle aspiration of thyroid nodules: proteomic analysis to identify cancer biomarkers. J. Proteome Res. 7, 4079–4088 (2008).

  19. 19.

    & Glycolytic cancer cells lacking 6-phosphogluconate dehydrogenase metabolize glucose to induce senescence. FEBS Lett. 586, 2389–2395 (2012).

  20. 20.

    , & 6-Phosphogluconate dehydrogenase regulates tumor cell migration in vitro by regulating receptor tyrosine kinase c-Met. Biochem. Biophys. Res. Commun. 439, 247–251 (2013).

  21. 21.

    et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl Acad. Sci. USA 101, 3329–3335 (2004).

  22. 22.

    et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004–2008 (2003).

  23. 23.

    & The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. Cancer 9, 563–575 (2009).

  24. 24.

    et al. Phosphorylation-activity relationships of AMPK and acetyl-CoA carboxylase in muscle. J. Appl. Physiol. 92, 2475–2482 (2002).

  25. 25.

    Regulation of fatty-acid and cholesterol-metabolism by the AMP-activated protein-kinase. Biochim. Biophys. Acta 1123, 231–238 (1992).

  26. 26.

    , & AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012).

  27. 27.

    et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat. Med. 19, 1649–1654 (2013).

  28. 28.

    & Regulation of hepatic phosphofructokinase by 6-phosphogluconate. J. Biol. Chem. 257, 9424–9428 (1982).

  29. 29.

    , & Location and function of three sites phosphorylated on rat acetyl-CoA carboxylase by the AMP-activated protein kinase. Eur. J. Biochem. 187, 183–190 (1990).

  30. 30.

    , , & Critical phosphorylation sites for acetyl-CoA carboxylase activity. J. Biol. Chem. 269, 22162–22168 (1994).

  31. 31.

    , , , & High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5′-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J. Biol. Chem. 270, 17513–17520 (1995).

  32. 32.

    , , & Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. Eur. J. Biochem. 175, 331–338 (1988).

  33. 33.

    & The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13, 1016–1023 (2011).

  34. 34.

    et al. MO25α/β interact with STRADα/β enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. EMBO J. 22, 5102–5114 (2003).

  35. 35.

    , , , & Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science 326, 1707–1711 (2009).

  36. 36.

    et al. Novel splice isoforms of STRADα differentially affect LKB1 activity, complex assembly and subcellular localization. Cancer Biol. Ther. 6, 1627–1631 (2007).

  37. 37.

    et al. Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth. Mol. Cell 55, 552–565 (2014).

  38. 38.

    et al. Tyrosine phosphorylation of lactate dehydrogenase A is important for NADH/NAD(+) redox homeostasis in cancer cells. Mol. Cell. Biol. 31, 4938–4950 (2011).

  39. 39.

    et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol. Cell 53, 534–548 (2014).

  40. 40.

    et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol. Cell 44, 864–877 (2011).

  41. 41.

    et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci. Signal. 2, ra73 (2009).

  42. 42.

    et al. Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation. Nat. Commun. 4, 1790 (2013).

  43. 43.

    et al. Tyr-94 phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth. J. Biol. Chem. 289, 21413–21422 (2014).

  44. 44.

    et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 337, 975–980 (2012).

  45. 45.

    et al. Differential regulation of phosphoglucose isomerase/autocrine motility factor activities by protein kinase CK2 phosphorylation. J. Biol. Chem. 280, 10419–10426 (2005).

  46. 46.

    et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324, 261–265 (2009).

  47. 47.

    et al. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol. Cell 51, 506–518 (2013).

  48. 48.

    , , & Oleic acid is a potent inhibitor of fatty acid and cholesterol synthesis in C6 glioma cells. J. Lipid Res. 48, 1966–1975 (2007).

  49. 49.

    , , & Critical role of arg433 in rat transketolase activity as probed by site-directed mutagenesis. Biochem. J. 333, 367–372 (1998).

  50. 50.

    , & A novel assay system for the measurement of transketolase activity using xylulokinase from Saccharomyces cerevisiae. Biotechnol. Lett. 30, 899–904 (2008).

  51. 51.

    et al. Cordycepin activates AMP-activated protein kinase (AMPK) via interaction with the γ1 subunit. J. Cell. Mol. Med. 18, 293–304 (2014).

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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.


  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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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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