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; 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

doi:10.1038/ncb3255

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 MaoPeng 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

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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 language	English (US)
Pages (from-to)	1484-1496
Number of pages	13
Journal	Nature cell biology
Volume	17
Issue number	11
DOIs	https://doi.org/10.1038/ncb3255
State	Published - Nov 1 2015

ASJC Scopus subject areas

Cell Biology

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Lin, R., Elf, S., Shan, C., Kang, H. B., Ji, Q., Zhou, L., Hitosugi, T., Zhang, L., Zhang, S., Seo, J. H., Xie, J., Tucker, M., Gu, T. L., Sudderth, J., Jiang, L., Mitsche, M., DeBerardinis, R. J., Wu, S., Li, Y., ... Chen, J. (2015). 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. Nature cell biology, 17(11), 1484-1496. https://doi.org/10.1038/ncb3255

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

@article{0790c6a7687e4563b3546337ebcaa2b1,

title = "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.",

author = "Ruiting Lin and Shannon Elf and Changliang Shan and Kang, {Hee Bum} and Quanjiang Ji and Lu Zhou and Taro Hitosugi and Liang Zhang and Shuai Zhang and Seo, {Jae Ho} and Jianxin Xie and Meghan Tucker and Gu, {Ting Lei} and Jessica Sudderth and Lei Jiang and Matthew Mitsche and DeBerardinis, {Ralph J.} and Shaoxiong Wu and Yuancheng Li and Hui Mao and Chen, {Peng R.} and Dongsheng Wang and Chen, {Georgia Zhuo} and Hurwitz, {Selwyn J.} and Sagar Lonial and Arellano, {Martha L.} and Khoury, {Hanna J.} and Khuri, {Fadlo R.} and Lee, {Benjamin H.} and Qunying Lei and Brat, {Daniel J.} and Keqiang Ye and Boggon, {Titus J.} and Chuan He and Sumin Kang and Jun Fan and Jing Chen",

note = "Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = nov,

day = "1",

doi = "10.1038/ncb3255",

language = "English (US)",

volume = "17",

pages = "1484--1496",

journal = "Nature cell biology",

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T1 - 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling

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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M3 - Article

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SN - 1465-7392

VL - 17

SP - 1484

EP - 1496

JO - Nature cell biology

JF - Nature cell biology

IS - 11

ER -

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

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