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; Tsuyoshi Osawa

doi:10.1038/s41467-022-31418-w

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.

Authors

Melvin Pan¹, Christiane Zorbas², Maki Sugaya¹, Kensuke Ishiguro^{3

4}, Miki Kato¹, Miyuki Nishida¹, Hai-Feng Zhang^{5

6}, Marco M Candeias⁷, Akimitsu Okamoto³, Takamasa Ishikawa⁸, Tomoyoshi Soga⁸, Hiroyuki Aburatani⁹, Juro Sakai^{10

11}, Yoshihiro Matsumura^{10

11}, Tsutomu Suzuki³, Christopher G Proud^{12

13}, Denis L J Lafontaine², 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. osawa@lsbm.org.
¹⁵ Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, 113-8656, Japan. osawa@lsbm.org.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Glutamine* / metabolism
Humans
Neoplasms* / genetics
Neoplasms* / metabolism
Nucleic Acid Synthesis Inhibitors
RNA Precursors / metabolism
RNA, Ribosomal / genetics
RNA, Ribosomal / metabolism
Ribosomes / metabolism
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Nucleic Acid Synthesis Inhibitors
RNA Precursors
RNA, Ribosomal
Tumor Suppressor Protein p53
Glutamine