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

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 & 17 others 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1484-1496
Number of pages13
JournalNature Cell Biology
Volume17
Issue number11
DOIs
StatePublished - Nov 1 2015

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Phosphogluconate Dehydrogenase
Pentose Phosphate Pathway
Lipogenesis
AMP-Activated Protein Kinases
Growth
Neoplasms
Cell Proliferation
Acetyl-CoA Carboxylase
RNA Precursors
NADP
Heterografts
Nude Mice
Carcinogenesis
RNA
Enzymes
ribulose 5-phosphate

ASJC Scopus subject areas

  • Cell Biology

Cite this

6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. / 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; Fan, Jun; Chen, Jing.

In: Nature Cell Biology, Vol. 17, No. 11, 01.11.2015, p. 1484-1496.

Research output: Contribution to journalArticle

Lin, R, Elf, S, Shan, C, Kang, HB, Ji, Q, Zhou, L, Hitosugi, T, Zhang, L, Zhang, S, Seo, JH, Xie, J, Tucker, M, Gu, TL, Sudderth, J, Jiang, L, Mitsche, M, DeBerardinis, RJ, Wu, S, Li, Y, Mao, H, Chen, PR, Wang, D, Chen, GZ, Hurwitz, SJ, Lonial, S, Arellano, ML, Khoury, HJ, Khuri, FR, Lee, BH, Lei, Q, Brat, DJ, Ye, K, Boggon, TJ, He, C, Kang, S, Fan, J & Chen, J 2015, '6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling', Nature Cell Biology, vol. 17, no. 11, pp. 1484-1496. https://doi.org/10.1038/ncb3255
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 ; Fan, Jun ; Chen, Jing. / 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. In: Nature Cell Biology. 2015 ; Vol. 17, No. 11. pp. 1484-1496.
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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.",
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AU - Lin, Ruiting

AU - Elf, Shannon

AU - Shan, Changliang

AU - Kang, Hee Bum

AU - Ji, Quanjiang

AU - Zhou, Lu

AU - Hitosugi, Taro

AU - Zhang, Liang

AU - Zhang, Shuai

AU - Seo, Jae Ho

AU - Xie, Jianxin

AU - Tucker, Meghan

AU - Gu, Ting Lei

AU - Sudderth, Jessica

AU - Jiang, Lei

AU - Mitsche, Matthew

AU - DeBerardinis, Ralph J.

AU - Wu, Shaoxiong

AU - Li, Yuancheng

AU - Mao, Hui

AU - Chen, Peng R.

AU - Wang, Dongsheng

AU - Chen, Georgia Zhuo

AU - Hurwitz, Selwyn J.

AU - Lonial, Sagar

AU - Arellano, Martha L.

AU - Khoury, Hanna J.

AU - Khuri, Fadlo R.

AU - Lee, Benjamin H.

AU - Lei, Qunying

AU - Brat, Daniel J.

AU - Ye, Keqiang

AU - Boggon, Titus J.

AU - He, Chuan

AU - Kang, Sumin

AU - Fan, Jun

AU - Chen, Jing

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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.

AB - 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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