IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-38594-3.html
   My bibliography  Save this article

Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss

Author

Listed:
  • Xianbing Zhu

    (McGill University
    McGill University)

  • Zheng Fu

    (McGill University
    McGill University)

  • Shary Y. Chen

    (University of British Columbia
    British Columbia Cancer Research Institute)

  • Dionzie Ong

    (University of British Columbia)

  • Giulio Aceto

    (McGill University
    McGill University)

  • Rebecca Ho

    (University of British Columbia
    British Columbia Cancer Research Institute)

  • Jutta Steinberger

    (McGill University
    McGill University)

  • Anie Monast

    (McGill University
    McGill University)

  • Virginie Pilon

    (McGill University
    McGill University)

  • Eunice Li

    (University of British Columbia)

  • Monica Ta

    (University of British Columbia)

  • Kyle Ching

    (University of British Columbia)

  • Bianca N. Adams

    (McGill University
    McGill University)

  • Gian L. Negri

    (British Columbia Cancer Research Institute)

  • Luc Choiniere

    (McGill University)

  • Lili Fu

    (McGill University Health Centre)

  • Kitty Pavlakis

    (IASO women’s hospital)

  • Patrick Pirrotte

    (Translational Genomics Research Institute
    City of Hope Comprehensive Cancer Center)

  • Daina Z. Avizonis

    (McGill University)

  • Jeffrey Trent

    (Division of Integrated Cancer Genomics)

  • Bernard E. Weissman

    (University of North Carolina
    University of North Carolina)

  • Ramon I. Klein Geltink

    (University of British Columbia)

  • Gregg B. Morin

    (British Columbia Cancer Research Institute
    University of British Columbia)

  • Morag Park

    (McGill University
    McGill University)

  • David G. Huntsman

    (University of British Columbia
    British Columbia Cancer Research Institute
    University of British Columbia)

  • William D. Foulkes

    (Medicine and Oncology McGill University
    McGill University Health Centre
    McGill University)

  • Yemin Wang

    (University of British Columbia
    British Columbia Cancer Research Institute)

  • Sidong Huang

    (McGill University
    McGill University)

Abstract

SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4/2 occurs in a subset of cancers associated with very poor outcomes. Here, we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deficient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers.

Suggested Citation

  • Xianbing Zhu & Zheng Fu & Shary Y. Chen & Dionzie Ong & Giulio Aceto & Rebecca Ho & Jutta Steinberger & Anie Monast & Virginie Pilon & Eunice Li & Monica Ta & Kyle Ching & Bianca N. Adams & Gian L. Ne, 2023. "Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38594-3
    DOI: 10.1038/s41467-023-38594-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-38594-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-38594-3?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. Yibo Xue & Jordan L. Morris & Kangning Yang & Zheng Fu & Xianbing Zhu & Fraser Johnson & Brian Meehan & Leora Witkowski & Amber Yasmeen & Tunde Golenar & Mackenzie Coatham & Geneviève Morin & Anie Mon, 2021. "SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca2+ flux to mitochondria," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    2. Cristovão M. Sousa & Douglas E. Biancur & Xiaoxu Wang & Christopher J. Halbrook & Mara H. Sherman & Li Zhang & Daniel Kremer & Rosa F. Hwang & Agnes K. Witkiewicz & Haoqiang Ying & John M. Asara & Ron, 2016. "Erratum: Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion," Nature, Nature, vol. 540(7631), pages 150-150, December.
    3. Tharu M. Fernando & Robert Piskol & Russell Bainer & Ethan S. Sokol & Sally E. Trabucco & Qing Zhang & Huong Trinh & Sophia Maund & Marc Kschonsak & Subhra Chaudhuri & Zora Modrusan & Thomas Januario , 2020. "Functional characterization of SMARCA4 variants identified by targeted exome-sequencing of 131,668 cancer patients," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    4. Silvia Domcke & Rileen Sinha & Douglas A. Levine & Chris Sander & Nikolaus Schultz, 2013. "Evaluating cell lines as tumour models by comparison of genomic profiles," Nature Communications, Nature, vol. 4(1), pages 1-10, October.
    5. Kıvanç Birsoy & Richard Possemato & Franziska K. Lorbeer & Erol C. Bayraktar & Prathapan Thiru & Burcu Yucel & Tim Wang & Walter W. Chen & Clary B. Clish & David M. Sabatini, 2014. "Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides," Nature, Nature, vol. 508(7494), pages 108-112, April.
    6. Cristovão M. Sousa & Douglas E. Biancur & Xiaoxu Wang & Christopher J. Halbrook & Mara H. Sherman & Li Zhang & Daniel Kremer & Rosa F. Hwang & Agnes K. Witkiewicz & Haoqiang Ying & John M. Asara & Ron, 2016. "Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion," Nature, Nature, vol. 536(7617), pages 479-483, August.
    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. 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.
    2. Nneka E. Mbah & Amy L. Myers & Peter Sajjakulnukit & Chan Chung & Joyce K. Thompson & Hanna S. Hong & Heather Giza & Derek Dang & Zeribe C. Nwosu & Mengrou Shan & Stefan R. Sweha & Daniella D. Maydan , 2024. "Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Yuying Tan & Junjie Li & Guangyuan Zhao & Kai-Chih Huang & Horacio Cardenas & Yinu Wang & Daniela Matei & Ji-Xin Cheng, 2022. "Metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation in platinum-resistant cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Jun Dai & Shuyu Zheng & Matías M. Falco & Jie Bao & Johanna Eriksson & Sanna Pikkusaari & Sofia Forstén & Jing Jiang & Wenyu Wang & Luping Gao & Fernando Perez-Villatoro & Olli Dufva & Khalid Saeed & , 2024. "Tracing back primed resistance in cancer via sister cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Shuaifeng Li & Shixun Han & Qi Zhang & Yibing Zhu & Haitao Zhang & Junli Wang & Yang Zhao & Jianhui Zhao & Lin Su & Li Li & Dawang Zhou & Cunqi Ye & Xin-Hua Feng & Tingbo Liang & Bin Zhao, 2022. "FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Elena Giudice & Tzu-Ting Huang & Jayakumar R. Nair & Grant Zurcher & Ann McCoy & Darryl Nousome & Marc R. Radke & Elizabeth M. Swisher & Stanley Lipkowitz & Kristen Ibanez & Duncan Donohue & Tyler Mal, 2024. "The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Yuanli Zhen & Kai Liu & Lei Shi & Simran Shah & Qin Xu & Haley Ellis & Eranga R. Balasooriya & Johannes Kreuzer & Robert Morris & Albert S. Baldwin & Dejan Juric & Wilhelm Haas & Nabeel Bardeesy, 2024. "FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Yurou Chen & Yulong Qiang & Jiachen Fan & Qian Zheng & Leilei Yan & Guanlan Fan & Xiaofei Song & Nan Zhang & Qiongying Lv & Jiaqiang Xiong & Jingtao Wang & Jing Cao & Yanyan Liu & Jie Xiong & Wei Zhan, 2024. "Aggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    9. Xiaohang Yang & Xingyuan Hu & Jingjing Yin & Wenting Li & Yu Fu & Bin Yang & Junpeng Fan & Funian Lu & Tianyu Qin & Xiaoyan Kang & Xucui Zhuang & Fuxia Li & Rourou Xiao & Tingyan Shi & Kun Song & Jing, 2024. "Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    10. Natasha Ramakrishnan & Tyler M. Weaver & Lindsey N. Aubuchon & Ayda Woldegerima & Taylor Just & Kevin Song & Alessandro Vindigni & Bret D. Freudenthal & Priyanka Verma, 2024. "Nucleolytic processing of abasic sites underlies PARP inhibitor hypersensitivity in ALC1-deficient BRCA mutant cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Xin Yuan & Yanran Ma & Ruitian Gao & Shuya Cui & Yifan Wang & Botao Fa & Shiyang Ma & Ting Wei & Shuangge Ma & Zhangsheng Yu, 2024. "HEARTSVG: a fast and accurate method for identifying spatially variable genes in large-scale spatial transcriptomics," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    12. Marc Hennequart & Christiaan F. Labuschagne & Mylène Tajan & Steven E. Pilley & Eric C. Cheung & Nathalie M. Legrave & Paul C. Driscoll & Karen H. Vousden, 2021. "The impact of physiological metabolite levels on serine uptake, synthesis and utilization in cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-10, December.

    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:14:y:2023:i:1:d:10.1038_s41467-023-38594-3. 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.