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

  • Nat Commun. 2022 Jun 28;13(1):3706. doi: 10.1038/s41467-022-31418-w.
Melvin Pan  1 ,  Christiane Zorbas  2 ,  Maki Sugaya  1 ,  Kensuke Ishiguro  3  4 ,  Miki Kato  1 ,  Miyuki Nishida  1 ,  Hai-Feng Zhang  5  6 ,  Marco M Candeias  7 ,  Akimitsu Okamoto  3 ,  Takamasa Ishikawa  8 ,  Tomoyoshi Soga  8 ,  Hiroyuki Aburatani  9 ,  Juro Sakai  10  11 ,  Yoshihiro Matsumura  10  11 ,  Tsutomu Suzuki  3 ,  Christopher G Proud  12  13 ,  Denis L J Lafontaine  2 ,  Tsuyoshi Osawa  14  15
Affiliations
  • 1. Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
  • 2. RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S.-FNRS), Université Libre de Bruxelles (ULB), Biopark campus, 6041, Gosselies, Belgium.
  • 3. Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, 113-8656, Japan.
  • 4. RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
  • 5. Department of Molecular Oncology, BC Cancer, Vancouver, BC, V5Z 1L3, Canada.
  • 6. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada.
  • 7. Molecular and RNA Cancer Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 8. Institute for Advanced Biosciences, Keio University, Tsuruoka, 997-0052, Japan.
  • 9. Genome Science Division, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
  • 10. Division of Metabolic Medicine, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
  • 11. Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
  • 12. Lifelong Health, South Australian Health & Medical Research Institute, Adelaide, SA, 5000, Australia.
  • 13. School of Biomedical Sciences, University of Adelaide, Adelaide, SA, 5005, Australia.
  • 14. Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan. [email protected].
  • 15. Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, 113-8656, Japan. [email protected].
PMID: 35764642 DOI: 10.1038/s41467-022-31418-w
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.

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