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Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors

Author

Listed:
  • Melvin Pan

    (The University of Tokyo)

  • Christiane Zorbas

    (Université Libre de Bruxelles (ULB), Biopark campus)

  • Maki Sugaya

    (The University of Tokyo)

  • Kensuke Ishiguro

    (The University of Tokyo
    RIKEN Center for Biosystems Dynamics Research)

  • Miki Kato

    (The University of Tokyo)

  • Miyuki Nishida

    (The University of Tokyo)

  • Hai-Feng Zhang

    (Department of Molecular Oncology, BC Cancer
    University of British Columbia)

  • Marco M. Candeias

    (Kyoto University)

  • Akimitsu Okamoto

    (The University of Tokyo)

  • Takamasa Ishikawa

    (Keio University)

  • Tomoyoshi Soga

    (Keio University)

  • Hiroyuki Aburatani

    (The University of Tokyo)

  • Juro Sakai

    (The University of Tokyo
    Tohoku University Graduate School of Medicine)

  • Yoshihiro Matsumura

    (The University of Tokyo
    Tohoku University Graduate School of Medicine)

  • Tsutomu Suzuki

    (The University of Tokyo)

  • Christopher G. Proud

    (South Australian Health & Medical Research Institute
    University of Adelaide)

  • Denis L. J. Lafontaine

    (Université Libre de Bruxelles (ULB), Biopark campus)

  • Tsuyoshi Osawa

    (The University of Tokyo
    The University of Tokyo)

Abstract

Ribosome biogenesis is an energetically expensive program that is dictated by nutrient availability. Here we report that nutrient deprivation severely impairs precursor ribosomal RNA (pre-rRNA) processing and leads to the accumulation of unprocessed rRNAs. Upon nutrient restoration, pre-rRNAs stored under starvation are processed into mature rRNAs that are utilized for ribosome biogenesis. Failure to accumulate pre-rRNAs under nutrient stress leads to perturbed ribosome assembly upon nutrient restoration and subsequent apoptosis via uL5/uL18-mediated activation of p53. Restoration of glutamine alone activates p53 by triggering uL5/uL18 translation. Induction of uL5/uL18 protein synthesis by glutamine is dependent on the translation factor eukaryotic elongation factor 2 (eEF2), which is in turn dependent on Raf/MEK/ERK signaling. Depriving cells of glutamine prevents the activation of p53 by rRNA synthesis inhibitors. Our data reveals a mechanism that tumor cells can exploit to suppress p53-mediated apoptosis during fluctuations in environmental nutrient availability.

Suggested Citation

  • Melvin Pan & Christiane Zorbas & Maki Sugaya & Kensuke Ishiguro & Miki Kato & Miyuki Nishida & Hai-Feng Zhang & Marco M. Candeias & Akimitsu Okamoto & Takamasa Ishikawa & Tomoyoshi Soga & Hiroyuki Abu, 2022. "Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31418-w
    DOI: 10.1038/s41467-022-31418-w
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    References listed on IDEAS

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