| Title | 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling |
| Authors | Lin, Ruiting Elf, Shannon Shan, Changliang Kang, Hee-Bum Ji, Quanjiang Zhou, Lu Hitosugi, Taro Zhang, Liang Zhang, Shuai Seo, Jae Ho Xie, Jianxin Tucker, Meghan Gu, Ting-Lei Sudderth, Jessica Jiang, Lei Mitsche, Matthew DeBerardinis, Ralph J. Wu, Shaoxiong Li, Yuancheng Mao, Hui Chen, Peng R. Wang, Dongsheng Chen, Georgia Zhuo Hurwitz, Selwyn J. Lonial, Sagar Arellano, Martha L. Khoury, Hanna J. Khuri, Fadlo R. Lee, Benjamin H. Lei, Qunying Brat, Daniel J. Ye, Keqiang Boggon, Titus J. He, Chuan Kang, Sumin |
| Affiliation | Emory Univ, Sch Med, Winship Canc Inst Emory, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. Univ Chicago, Dept Chem, Chicago, IL 60637 USA. Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA. Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. Cell Signaling Technol Inc, Danvers, MA 01923 USA. Univ Texas SW Med Ctr Dallas, Childrens Res Inst, Dallas, TX 75390 USA. Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA. Emory Univ, Sch Med, Dept Chem, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Radiol, Atlanta, GA 30322 USA. Peking Univ, Coll Chem & Mol Engn, Beijing 100871, Peoples R China. Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. Novartis Inst BioMed Res, Cambridge, MA 02139 USA. Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China. Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA. |
| Keywords | ACETYL-COA CARBOXYLASE ACTIVATED PROTEIN-KINASE PHOSPHORYLATION SITES GLUCOSE-6-PHOSPHATE-DEHYDROGENASE ACTIVITY CELL METABOLISM ENERGY STRESS CANCER-CELLS FATTY-ACID IN-SITU LKB1 |
| Issue Date | 2015 |
| Publisher | NATURE CELL BIOLOGY |
| Citation | NATURE CELL BIOLOGY.2015,17,(11),1484-1496. |
| 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. |
| URI | http://hdl.handle.net/20.500.11897/415392 |
| ISSN | 1465-7392 |
| DOI | 10.1038/ncb3255 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | å å¦ä¸ å å å·¥ç¨ å¦é ¢ |
