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Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor

Author

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  • Abigail S. Krall

    (David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA)

  • Shili Xu

    (David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA)

  • Thomas G. Graeber

    (David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA
    Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA
    Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, 650 Charles East Young Drive South, Los Angeles, California 90095, USA
    UCLA Metabolomics Center, 650 Charles East Young Drive South, Los Angeles, California 90095, USA)

  • Daniel Braas

    (David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA
    UCLA Metabolomics Center, 650 Charles East Young Drive South, Los Angeles, California 90095, USA)

  • Heather R. Christofk

    (David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA
    Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, 650 Charles East Young Drive South, Los Angeles, California 90095, USA
    UCLA Metabolomics Center, 650 Charles East Young Drive South, Los Angeles, California 90095, USA
    Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA)

Abstract

Cellular amino acid uptake is critical for mTOR complex 1 (mTORC1) activation and cell proliferation. However, the regulation of amino acid uptake is not well-understood. Here we describe a role for asparagine as an amino acid exchange factor: intracellular asparagine exchanges with extracellular amino acids. Through asparagine synthetase knockdown and altering of media asparagine concentrations, we show that intracellular asparagine levels regulate uptake of amino acids, especially serine, arginine and histidine. Through its exchange factor role, asparagine regulates mTORC1 activity and protein synthesis. In addition, we show that asparagine regulation of serine uptake influences serine metabolism and nucleotide synthesis, suggesting that asparagine is involved in coordinating protein and nucleotide synthesis. Finally, we show that maintenance of intracellular asparagine levels is critical for cancer cell growth. Collectively, our results indicate that asparagine is an important regulator of cancer cell amino acid homeostasis, anabolic metabolism and proliferation.

Suggested Citation

  • Abigail S. Krall & Shili Xu & Thomas G. Graeber & Daniel Braas & Heather R. Christofk, 2016. "Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11457
    DOI: 10.1038/ncomms11457
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    Cited by:

    1. Qiming Zhou & Yao Peng & Fenfen Ji & Huarong Chen & Wei Kang & Lam-Shing Chan & Hongyan Gou & Yufeng Lin & Pingmei Huang & Danyu Chen & Qinyao Wei & Hao Su & Cong Liang & Xiang Zhang & Jun Yu & Chi Ch, 2023. "Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Yubo Shen & Huifang Wang & Daoxia Guo & Jiantao Liu & Jinli Sun & Nan Chen & Haiyun Song & Xiaoyuan Ji, 2025. "Dual asparagine-depriving nanoparticles against solid tumors," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    3. Anaïs Aussel & Ivan Nemazanyy & Ashaina Vandenberghe & Pauline Meola & Noémie Dorat & Rachel Paul & Lama Habbouche & Laurie Exposito & Nicolas Nottet & Virginie Petrilli & Edmond Chiche & Nicolas Moun, 2026. "Tumor metabolic adaptation induced by L-asparaginase reveals a vulnerability to PARP1/2 inhibitor in B-cell lymphomas," Nature Communications, Nature, vol. 17(1), pages 1-21, December.
    4. Rens Peeters & Jorge Cuenca-Escalona & Esther A. Zaal & Anna T. Hoekstra & Anouk C. G. Balvert & Marcos Vidal-Manrique & Niek Blomberg & Sjoerd J. Deventer & Rinke Stienstra & Julia Jellusova & Martin, 2022. "Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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