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

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

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研究成果: Article › 査読

6 被引用数 (Scopus)

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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.

本文言語	English
論文番号	3706
ジャーナル	Nature communications
巻	13
号	1
DOI	https://doi.org/10.1038/s41467-022-31418-w
出版ステータス	Published - 2022 12月

ASJC Scopus subject areas

物理学および天文学（全般）
化学 (全般)
生化学、遺伝学、分子生物学（全般）

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10.1038/s41467-022-31418-w

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Pan, M., Zorbas, C., Sugaya, M., Ishiguro, K., Kato, M., Nishida, M., Zhang, H. F., Candeias, M. M., Okamoto, A., Ishikawa, T., Soga, T., Aburatani, H., Sakai, J., Matsumura, Y., Suzuki, T., Proud, C. G., Lafontaine, D. L. J., & Osawa, T. (2022). Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors. Nature communications, 13(1), Article 3706. https://doi.org/10.1038/s41467-022-31418-w

Pan, M, Zorbas, C, Sugaya, M, Ishiguro, K, Kato, M, Nishida, M, Zhang, HF, Candeias, MM, Okamoto, A, Ishikawa, T, Soga, T, Aburatani, H, Sakai, J, Matsumura, Y, Suzuki, T, Proud, CG, Lafontaine, DLJ & Osawa, T 2022, 'Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors', Nature communications, vol. 13, no. 1, 3706. https://doi.org/10.1038/s41467-022-31418-w

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title = "Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors",

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.",

author = "Melvin Pan and Christiane Zorbas and Maki Sugaya and Kensuke Ishiguro and Miki Kato and Miyuki Nishida and Zhang, {Hai Feng} and Candeias, {Marco M.} and Akimitsu Okamoto and Takamasa Ishikawa and Tomoyoshi Soga and Hiroyuki Aburatani and Juro Sakai and Yoshihiro Matsumura and Tsutomu Suzuki and Proud, {Christopher G.} and Lafontaine, {Denis L.J.} and Tsuyoshi Osawa",

note = "Funding Information: We thank the members of the Laboratory for Systems Biology and Medicine and Integrative Nutriomics and Oncology, RCAST, the University of Tokyo. We especially thank Dr. Shintaro Iwasaki and Dr. T. Tanaka for helpful discussions. This work was supported by Grant-in-Aid for Scientific Research B (19H03496, T.O.), Scientific Research on Innovative Areas (20H04834, T.O.) and Grant-in-Aid for challenging Exploratory Research (19K22553, 21K19399, T.O.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, The Tokyo Biochemical Research Foundation (T.O.), Life Science Foundation of Japan (T.O.), Princess Takamatsu Cancer research Found (T.O.), The Naito Foundation (T.O.), The Uehara Memorial Foundation (T.O.). Funding Information: We thank the members of the Laboratory for Systems Biology and Medicine and Integrative Nutriomics and Oncology, RCAST, the University of Tokyo. We especially thank Dr. Shintaro Iwasaki and Dr. T. Tanaka for helpful discussions. This work was supported by Grant-in-Aid for Scientific Research B (19H03496, T.O.), Scientific Research on Innovative Areas (20H04834, T.O.) and Grant-in-Aid for challenging Exploratory Research (19K22553, 21K19399, T.O.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, The Tokyo Biochemical Research Foundation (T.O.), Life Science Foundation of Japan (T.O.), Princess Takamatsu Cancer research Found (T.O.), The Naito Foundation (T.O.), The Uehara Memorial Foundation (T.O.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-31418-w",

language = "English",

volume = "13",

journal = "Nature communications",

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T1 - Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors

AU - Pan, Melvin

AU - Zorbas, Christiane

AU - Sugaya, Maki

AU - Ishiguro, Kensuke

AU - Kato, Miki

AU - Nishida, Miyuki

AU - Zhang, Hai Feng

AU - Candeias, Marco M.

AU - Okamoto, Akimitsu

AU - Ishikawa, Takamasa

AU - Soga, Tomoyoshi

AU - Aburatani, Hiroyuki

AU - Sakai, Juro

AU - Matsumura, Yoshihiro

AU - Suzuki, Tsutomu

AU - Proud, Christopher G.

AU - Lafontaine, Denis L.J.

AU - Osawa, Tsuyoshi

N1 - Funding Information: We thank the members of the Laboratory for Systems Biology and Medicine and Integrative Nutriomics and Oncology, RCAST, the University of Tokyo. We especially thank Dr. Shintaro Iwasaki and Dr. T. Tanaka for helpful discussions. This work was supported by Grant-in-Aid for Scientific Research B (19H03496, T.O.), Scientific Research on Innovative Areas (20H04834, T.O.) and Grant-in-Aid for challenging Exploratory Research (19K22553, 21K19399, T.O.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, The Tokyo Biochemical Research Foundation (T.O.), Life Science Foundation of Japan (T.O.), Princess Takamatsu Cancer research Found (T.O.), The Naito Foundation (T.O.), The Uehara Memorial Foundation (T.O.). Funding Information: We thank the members of the Laboratory for Systems Biology and Medicine and Integrative Nutriomics and Oncology, RCAST, the University of Tokyo. We especially thank Dr. Shintaro Iwasaki and Dr. T. Tanaka for helpful discussions. This work was supported by Grant-in-Aid for Scientific Research B (19H03496, T.O.), Scientific Research on Innovative Areas (20H04834, T.O.) and Grant-in-Aid for challenging Exploratory Research (19K22553, 21K19399, T.O.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, The Tokyo Biochemical Research Foundation (T.O.), Life Science Foundation of Japan (T.O.), Princess Takamatsu Cancer research Found (T.O.), The Naito Foundation (T.O.), The Uehara Memorial Foundation (T.O.). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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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DO - 10.1038/s41467-022-31418-w

M3 - Article

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SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 3706

ER -

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

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