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

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 Aburatani, Juro Sakai, Yoshihiro Matsumura, Tsutomu Suzuki, Christopher G. Proud, Denis L. J. Lafontaine and Tsuyoshi Osawa ()
Additional contact information
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
Miki Kato: The University of Tokyo
Miyuki Nishida: The University of Tokyo
Hai-Feng Zhang: Department of Molecular Oncology, BC Cancer
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
Yoshihiro Matsumura: The University of Tokyo
Tsutomu Suzuki: The University of Tokyo
Christopher G. Proud: South Australian Health & Medical Research Institute
Denis L. J. Lafontaine: Université Libre de Bruxelles (ULB), Biopark campus
Tsuyoshi Osawa: The University of Tokyo

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31418-w

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