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Author Notes:

Correspondence should be addressed to S.K., J.F. or J.C. (smkang@emory.edu, jfan3@emory.edu, or jchen@emory.edu).

R.L., S.E., and C.S. contributed equally to this work.

J.X., T.-L.G., S.Z., K.Y., P.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 analyzed 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 analyzed 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.

The authors declare no competing financial interests.

Subjects:

Research Funding:

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.Z.), 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.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • ACETYL-COA CARBOXYLASE
  • ACTIVATED PROTEIN-KINASE
  • PHOSPHORYLATION SITES
  • GLUCOSE-6-PHOSPHATE-DEHYDROGENASE ACTIVITY
  • CELL METABOLISM
  • ENERGY STRESS
  • CANCER-CELLS
  • FATTY-ACID
  • IN-SITU
  • LKB1

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

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Journal Title:

Nature Cell Biology

Volume:

Volume 17, Number 11

Publisher:

, Pages 1484-1496

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2015 Macmillan Publishers Limited.

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