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

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

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. osawa@lsbm.org.
  • 15 Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, 113-8656, Japan. osawa@lsbm.org.
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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