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

par Pan, Melvin;Zorbas, Christiane ;Sugaya, Maki;Ishiguro, Kensuke;Kato, Miki;Nishida, Miyuki;Zhang, Hai Feng;Candeias, Marco M.M.;Okamoto, Akimitsu;Ishikawa, Takamasa;Soga, Tomoyoshi;Aburatani, Hiroyuki;Sakai, Juro;Matsumura, Yoshihiro;Suzuki, Tsutomu;Proud, Christopher Gregory;Lafontaine, Denis ;Osawa, Tsuyoshi
Référence Nature communications, 13, 1, 3706
Publication Publié, 2022-12

Article révisé par les pairs

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Résumé :

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.