6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1–AMPK signalling
Open accessAbstract
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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Multiple studies regard PGD as an anti-cancer target because PGD downregulation selectively inhibits the growth of various cancer cells through the AMPK pathway.
“Multiple studies regard PGD as an anti-cancer target as PGD downregulation selectively inhibits the growth of various cancer cells through AMPK pathway,130,131,132”
From Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators (2024) · cites this paper as [131]
The Results report that 6PGD knockdown reduced proliferation in several cancer cell lines but not control HaCaT cells, and that AMPK inhibition partly rescued reduced proliferation in H1299 cells. However, the Results also show that proliferation fell in LKB1-deficient A549 cells without a change in AMPK phosphorylation; antioxidant treatment rescued that effect. The AMPK mechanism therefore does not account for the growth inhibition in every cancer cell type studied. (LLM, conf=0.88)
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References 52 · Cited by 287
- Authors
- 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., Mao, H., Chen, P. R., Wang, D., Chen, G. Z., Hurwitz, S. J., Lonial, S., Arellano, M. L., Khoury, H. J., Khuri, F. R., Lee, B. H., Lei, Q., Brat, D. J., Ye, K., Boggon, T. J., He, C., Kang, S., Fan, J., & Chen, J.
- Affiliations
- Emory University (US)
- University of Chicago (US)
- Cell Signaling Technology (United States) (US)
- The University of Texas Southwestern Medical Center (US)
- Peking University (CN)
- Yale University (US)
- Corresponding author
- Kang, Sumin
- Fan, Jun
- Chen, Jing
- ORCID
- Elf, Shannon
- Shan, Changliang
- Kang, Hee-Bum
- Ji, Quanjiang
- Zhou, Lu
- Hitosugi, Taro
- Zhang, Liang
- Zhang, Shuai
- Seo, Jae Ho
- Xie, Jianxin
- Sudderth, Jessica
- Jiang, Lei
- Mitsche, Matthew
- DeBerardinis, Ralph J.
- Li, Yuancheng
- Mao, Hui
- Chen, Peng R.
- Wang, Dongsheng
- Lonial, Sagar
- Arellano, Martha L.
- Khuri, Fadlo R.
- Brat, Daniel J.
- Ye, Keqiang
- Boggon, Titus J.
- He, Chuan
- Kang, Sumin
- Fan, Jun
- Chen, Jing
- Venue
- Nature Cell Biology
- Published
- 2015-10-19
- Volume
- 17
- Issue
- 11
- Pages
- 1484-1496
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4628560
- OpenAlex
- W2112912738
- Cited by
- 287
- References
- 52
- Citations by year
- 2026: 18 · 2025: 18 · 2024: 36 · 2023: 28 · 2022: 32 · 2021: 39 · 2020: 29 · 2019: 28 · 2018: 27 · 2017: 15 · 2016: 17
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA174786, R01CA174786, CA183594, R01CA175316, CA175316, R01CA183594, CA140515, R01CA140515, P30CA138292)
- National Institute of General Medical Sciences (GM071440, R01GM071440, T32GM008602)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- 6-phosphogluconate dehydrogenase, oxidative pentose phosphate pathway, ribulose 5-phosphate, lipogenesis, acetyl-CoA carboxylase 1, tumor growth, reactive oxygen species, RNA synthesis, NADPH, physcion, cancer therapy targets, tumor cell proliferation
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Humans, Neoplasms, Pentose Phosphate Pathway, Phosphogluconate Dehydrogenase, Ribulosephosphates, Signal Transduction, Protein Serine-Threonine Kinases, Oxidative Stress, Lipogenesis, AMP-Activated Protein Kinases
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