6-phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumor growth by inhibiting LKB1-AMPK signaling
| Autor: | Lin, Ruiting, Elf, Shannon, Shan, Changliang, Kang, Hee-Bum, Ji, Quanjiang, Zhou, Lu, Hitosugi, Taro, Zhang, Liang, Zhang, Shuai, Ho Seo, Jae, 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, Khoury, Hanna J., Arellano, Martha L., Khuri, Fadlo R., Lee, Benjamin H., Lei, Qunying, Brat, Daniel J., Ye, Keqiang, Boggon, Titus J., He, Chuan, Kang, Sumin, Fan, Jun, Chen, Jing |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Oxidative phosphorylation
Pentose phosphate pathway AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Article Pentose Phosphate Pathway 03 medical and health sciences Ribulosephosphates 0302 clinical medicine AMP-activated protein kinase AMP-Activated Protein Kinase Kinases Neoplasms Humans Phosphogluconate dehydrogenase 030304 developmental biology 0303 health sciences biology Cell growth Lipogenesis Phosphogluconate Dehydrogenase AMPK Cell Biology 3. Good health Cell biology Oxidative Stress 030220 oncology & carcinogenesis Cancer cell biology.protein Signal Transduction |
| Zdroj: | Nature cell biology |
| ISSN: | 1476-4679 1465-7392 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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