IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-50157-8.html
   My bibliography  Save this article

Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer

Author

Listed:
  • Taijin Lan

    (Rutgers Cancer Institute)

  • Sara Arastu

    (Rutgers Cancer Institute)

  • Jarrick Lam

    (Rutgers Cancer Institute)

  • Hyungsin Kim

    (Rutgers Cancer Institute)

  • Wenping Wang

    (Rutgers Cancer Institute)

  • Samuel Wang

    (Rutgers Cancer Institute)

  • Vrushank Bhatt

    (Rutgers Cancer Institute)

  • Eduardo Cararo Lopes

    (Rutgers Cancer Institute
    Rutgers University)

  • Zhixian Hu

    (Rutgers Cancer Institute)

  • Michael Sun

    (Rutgers Cancer Institute)

  • Xuefei Luo

    (Rutgers Cancer Institute)

  • Jonathan M. Ghergurovich

    (Princeton University)

  • Xiaoyang Su

    (Rutgers Cancer Institute
    Rutgers Robert Wood Johnson Medical School)

  • Joshua D. Rabinowitz

    (Rutgers Cancer Institute
    Princeton University
    Princeton University
    Princeton University)

  • Eileen White

    (Rutgers Cancer Institute
    Rutgers University
    Princeton University)

  • Jessie Yanxiang Guo

    (Rutgers Cancer Institute
    Rutgers Robert Wood Johnson Medical School
    Rutgers Ernest Mario School of Pharmacy)

Abstract

Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NADPH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer mouse models, we show that G6PD ablation significantly suppresses KrasG12D/+;Lkb1-/- (KL) but not KrasG12D/+;P53-/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics reveal that G6PD ablation significantly impairs NADPH generation, redox balance, and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation activates p53, suppressing tumor growth. As tumors progress, G6PD-deficient KL tumors increase an alternative NADPH source from serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.

Suggested Citation

  • Taijin Lan & Sara Arastu & Jarrick Lam & Hyungsin Kim & Wenping Wang & Samuel Wang & Vrushank Bhatt & Eduardo Cararo Lopes & Zhixian Hu & Michael Sun & Xuefei Luo & Jonathan M. Ghergurovich & Xiaoyang, 2024. "Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50157-8
    DOI: 10.1038/s41467-024-50157-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-50157-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-50157-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Hongbin Ji & Matthew R. Ramsey & D. Neil Hayes & Cheng Fan & Kate McNamara & Piotr Kozlowski & Chad Torrice & Michael C. Wu & Takeshi Shimamura & Samanthi A. Perera & Mei-Chih Liang & Dongpo Cai & Geo, 2007. "LKB1 modulates lung cancer differentiation and metastasis," Nature, Nature, vol. 448(7155), pages 807-810, August.
    2. Anna Worthmann & Julius Ridder & Sharlaine Y. L. Piel & Ioannis Evangelakos & Melina Musfeldt & Hannah Voß & Marie O’Farrell & Alexander W. Fischer & Sangeeta Adak & Monica Sundd & Hasibullah Siffeti , 2024. "Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Sang-Min Jeon & Navdeep S. Chandel & Nissim Hay, 2012. "AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress," Nature, Nature, vol. 485(7400), pages 661-665, May.
    4. Sheng Hui & Jonathan M. Ghergurovich & Raphael J. Morscher & Cholsoon Jang & Xin Teng & Wenyun Lu & Lourdes A. Esparza & Tannishtha Reya & Le Zhan & Jessie Yanxiang Guo & Eileen White & Joshua D. Rabi, 2017. "Glucose feeds the TCA cycle via circulating lactate," Nature, Nature, vol. 551(7678), pages 115-118, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Ipshita Nandi & Linjia Ji & Harvey W. Smith & Daina Avizonis & Vasilios Papavasiliou & Cynthia Lavoie & Alain Pacis & Sherif Attalla & Virginie Sanguin-Gendreau & William J. Muller, 2024. "Targeting fatty acid oxidation enhances response to HER2-targeted therapy," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Charlotte M. François & Thomas Pihl & Marion Dunoyer de Segonzac & Chloé Hérault & Bruno Hudry, 2023. "Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Jayaraman, K. & Paramasivan, Lavinsaa & Kiumarsi, Shaian, 2017. "Reasons for low penetration on the purchase of photovoltaic (PV) panel system among Malaysian landed property owners," Renewable and Sustainable Energy Reviews, Elsevier, vol. 80(C), pages 562-571.
    4. Ali Vaziri-Gohar & Jonathan J. Hue & Ata Abbas & Hallie J. Graor & Omid Hajihassani & Mehrdad Zarei & George Titomihelakis & John Feczko & Moeez Rathore & Sylwia Chelstowska & Alexander W. Loftus & Ru, 2023. "Increased glucose availability sensitizes pancreatic cancer to chemotherapy," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Ji-Man Park & Da-Hye Lee & Do-Hyung Kim, 2023. "Redefining the role of AMPK in autophagy and the energy stress response," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Biaobin Jiang & Quanhua Mu & Fufang Qiu & Xuefeng Li & Weiqi Xu & Jun Yu & Weilun Fu & Yong Cao & Jiguang Wang, 2021. "Machine learning of genomic features in organotropic metastases stratifies progression risk of primary tumors," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    7. Wei Liu & Hongchao Cao & Jing Wang & Areeg Elmusrati & Bing Han & Wei Chen & Ping Zhou & Xiyao Li & Stephen Keysar & Antonio Jimeno & Cun-Yu Wang, 2024. "Histone-methyltransferase KMT2D deficiency impairs the Fanconi anemia/BRCA pathway upon glycolytic inhibition in squamous cell carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    8. Jin-Fei Lin & Ze-Xian Liu & Dong-Liang Chen & Ren-Ze Huang & Fen Cao & Kai Yu & Ting Li & Hai-Yu Mo & Hui Sheng & Zhi-Bing Liang & Kun Liao & Yi Han & Shan-Shan Li & Zhao-Lei Zeng & Song Gao & Huai-Qi, 2025. "Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    9. Sina Rhein & Riccardo Costalunga & Julica Inderhees & Tammo Gürtzgen & Teresa Christina Faupel & Zaib Shaheryar & Adriana Arrulo Pereira & Alaa Othman & Kimberly Begemann & Sonja Binder & Ines Stöltin, 2024. "The reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    10. Tal Levy & Kai Voeltzke & Laura Hruby & Khawla Alasad & Zuelal Bas & Marteinn Snaebjörnsson & Ran Marciano & Katerina Scharov & Mélanie Planque & Kim Vriens & Stefan Christen & Cornelius M. Funk & Chr, 2024. "mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    11. Christopher W. Murray & Jennifer J. Brady & Mingqi Han & Hongchen Cai & Min K. Tsai & Sarah E. Pierce & Ran Cheng & Janos Demeter & David M. Feldser & Peter K. Jackson & David B. Shackelford & Monte M, 2022. "LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    12. Xueman Chen & Rong Luo & Yunmei Zhang & Shuying Ye & Xin Zeng & Jiang Liu & Di Huang & Yujie Liu & Qiang Liu & Man-Li Luo & Erwei Song, 2022. "Long noncoding RNA DIO3OS induces glycolytic-dominant metabolic reprogramming to promote aromatase inhibitor resistance in breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    13. Dorothy Koveal & Paul C. Rosen & Dylan J. Meyer & Carlos Manlio Díaz-García & Yongcheng Wang & Li-Heng Cai & Peter J. Chou & David A. Weitz & Gary Yellen, 2022. "A high-throughput multiparameter screen for accelerated development and optimization of soluble genetically encoded fluorescent biosensors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    14. Juewon Kim & Yunju Jo & Gyumin Lim & Yosep Ji & Jong-Hwa Roh & Wan-Gi Kim & Hyon-Seung Yi & Dong Wook Choi & Donghyun Cho & Dongryeol Ryu, 2024. "A microbiota-derived metabolite, 3-phenyllactic acid, prolongs healthspan by enhancing mitochondrial function and stress resilience via SKN-1/ATFS-1 in C. elegans," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    15. Pierre Millard & Uwe Schmitt & Patrick Kiefer & Julia A Vorholt & Stéphanie Heux & Jean-Charles Portais, 2020. "ScalaFlux: A scalable approach to quantify fluxes in metabolic subnetworks," PLOS Computational Biology, Public Library of Science, vol. 16(4), pages 1-18, April.
    16. Guihong Lu & Xiaojun Wang & Feng Li & Shuang Wang & Jiawei Zhao & Jinyi Wang & Jing Liu & Chengliang Lyu & Peng Ye & Hui Tan & Weiping Li & Guanghui Ma & Wei Wei, 2022. "Engineered biomimetic nanoparticles achieve targeted delivery and efficient metabolism-based synergistic therapy against glioblastoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    17. Zhiyuan Cheng & Ning Cheng & Dian Shi & Xiaoyu Ren & Ting Gan & Yana Bai & Kehu Yang, 2019. "The Relationship between Nkx2.1 and DNA Oxidative Damage Repair in Nickel Smelting Workers: Jinchang Cohort Study," IJERPH, MDPI, vol. 16(1), pages 1-15, January.
    18. Yong Yi & Guoqiang Wang & Wenhua Zhang & Shuhan Yu & Junjie Fei & Tingting An & Jianqiao Yi & Fengtian Li & Ting Huang & Jian Yang & Mengmeng Niu & Yang Wang & Chuan Xu & Zhi-Xiong Jim Xiao, 2025. "Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    19. Andre Lima Queiroz & Ezequiel Dantas & Shakti Ramsamooj & Anirudh Murthy & Mujmmail Ahmed & Elizabeth R. M. Zunica & Roger J. Liang & Jessica Murphy & Corey D. Holman & Curtis J. Bare & Gregory Ghahra, 2022. "Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    20. Héctor García Martín & Vinay Satish Kumar & Daniel Weaver & Amit Ghosh & Victor Chubukov & Aindrila Mukhopadhyay & Adam Arkin & Jay D Keasling, 2015. "A Method to Constrain Genome-Scale Models with 13C Labeling Data," PLOS Computational Biology, Public Library of Science, vol. 11(9), pages 1-34, September.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50157-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.