@article{b7458e6645cb47e9a5a47be00801a76b,
title = "NRF3 activates mTORC1 arginine-dependently for cancer cell viability",
abstract = "Cancer cells coordinate the mTORC1 signals and the related metabolic pathways to robustly and rapidly grow in response to nutrient conditions. Although a CNC-family transcription factor NRF3 promotes cancer development, the biological relevance between NRF3 function and mTORC1 signals in cancer cells remains unknown. Hence, we showed that NRF3 contributes to cancer cell viability through mTORC1 activation in response to amino acids, particularly arginine. NRF3 induced SLC38A9 and RagC expression for the arginine-dependent mTORC1 recruitment onto lysosomes, and it also enhanced RAB5-mediated bulk macropinocytosis and SLC7A1-mediated selective transport for arginine loading into lysosomes. Besides, the inhibition of the NRF3–mTORC1 axis impaired mitochondrial function, leading to cancer cell apoptosis. Consistently, the aberrant upregulation of the axis caused tumor growth and poor prognosis. In conclusion, this study sheds light on the unique function of NRF3 in arginine-dependent mTORC1 activation and the pathophysiological aspects of the NRF3–mTORC1 axis in cancer development.",
keywords = "Cancer, Cell biology, Cellular physiology",
author = "Shuuhei Hirose and Tsuyoshi Waku and Misato Tani and Haruka Masuda and Keiko Endo and Sanae Ashitani and Iori Aketa and Hina Kitano and Sota Nakada and Ayaka Wada and Atsushi Hatanaka and Tsuyoshi Osawa and Tomoyoshi Soga and Akira Kobayashi",
note = "Funding Information: We are sincerely grateful to Ms. Saya Sato, Ms. Sanae Yamanaka, and Mr. Takamasa Ishikawa (Keio University) for the experimental support of metabolome analysis, and Dr. Hirokazu Nakatsumi (Nagoya City University) for critical suggestion of this study. We also thank Ms. Mika Matsumoto for the experimental support of flow cytometry and the Laboratory for Genetic Code members{\textquoteright} helpful discussions. This work was supported in part by grant-in-aid for JSPS Fellows (20J20194 to SH), a grant-in-aid for Scientific Research (C) (19K07650 and 22K07219 to TW); a grant-in-aid from the Inamori Foundation (to TW); a grant-in-aid from the Foundation for Promotion of Material Science and Technology of Japan (to TW); grant-in-aid for Scientific Research (B) (20H04135 to AK); grant-in-aid for Challenging Research (Exploratory) (21K19743 to AK); grant-in-aid for Scientific Research on Innovative Areas (22H04659 to AK); and grant-in-aid from the Mitsubishi Foundation (to AK). Conceptualization, S.H. and T.W.; Validation and Investigation, S.H. M.T. T.W. H.M. K.E. S.A. I.A. A.W. H.K. S.N. A.H. and T.O.; Writing – Original Draft and Visualization, S.H. and T.W.; Writing – Review and Editing, T.S. and A.K.; Supervision and Project administration, T.W.; Funding acquisition. S.H. T.W. and A.K. The authors declare no competing interests. Funding Information: We are sincerely grateful to Ms. Saya Sato, Ms. Sanae Yamanaka, and Mr. Takamasa Ishikawa (Keio University) for the experimental support of metabolome analysis, and Dr. Hirokazu Nakatsumi (Nagoya City University) for critical suggestion of this study. We also thank Ms. Mika Matsumoto for the experimental support of flow cytometry and the Laboratory for Genetic Code members{\textquoteright} helpful discussions. This work was supported in part by grant-in-aid for JSPS Fellows ( 20J20194 to SH), a grant-in-aid for Scientific Research (C) ( 19K07650 and 22K07219 to TW); a grant-in-aid from the Inamori Foundation (to TW); a grant-in-aid from the Foundation for Promotion of Material Science and Technology of Japan (to TW); grant-in-aid for Scientific Research (B) ( 20H04135 to AK); grant-in-aid for Challenging Research (Exploratory) ( 21K19743 to AK); grant-in-aid for Scientific Research on Innovative Areas ( 22H04659 to AK); and grant-in-aid from the Mitsubishi Foundation (to AK). Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = feb,
day = "17",
doi = "10.1016/j.isci.2023.106045",
language = "English",
volume = "26",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "2",
}
