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

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.

• Authors: Ruiting Lin, Shannon Elf, Changliang Shan, Hee-Bum Kang, Quanjiang Ji, Lu Zhou, Taro Hitosugi, Liang Zhang, Shuai Zhang, Jae Ho Seo, Jianxin Xie, Meghan Tucker, Ting-Lei Gu, Jessica Sudderth, Lei Jiang, Matthew Mitsche, Ralph J DeBerardinis, Shaoxiong Wu, Yuancheng Li, Hui Mao, Peng R Chen, Dongsheng Wang, Georgia Zhuo Chen, Selwyn J Hurwitz, Sagar Lonial, Martha L Arellano, Hanna J Khoury, Fadlo R Khuri, Benjamin H Lee, Qunying Lei, Daniel J Brat, Keqiang Ye, Titus J Boggon, Chuan He, Sumin Kang, Jun Fan, Jing Chen
• Journal: Nature cell biology (Nat Cell Biol) Vol. 17 Issue 11 Pg. 1484-96 (Nov 2015) ISSN: 1476-4679 [Electronic] England
• PMID: 26479318 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Review)

Chemical References

• Ribulosephosphates
• ribulose 5-phosphate
• Phosphogluconate Dehydrogenase
• Protein Serine-Threonine Kinases
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases (metabolism)
• Humans
• Lipogenesis
• Neoplasms (metabolism, pathology)
• Oxidative Stress
• Pentose Phosphate Pathway
• Phosphogluconate Dehydrogenase (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Ribulosephosphates (metabolism)
• Signal Transduction