NRF3 activates mTORC1 arginine-dependently for cancer cell viability
Shuuhei Hirose,
Tsuyoshi Waku,
Misato Tani,
Haruka Masuda,
Keiko Endo,
Sanae Ashitani,
Iori Aketa,
Hina Kitano,
Sota Nakada,
Ayaka Wada,
Atsushi Hatanaka,
Tsuyoshi Osawa,
Tomoyoshi Soga,
Akira Kobayashi
Affiliations
Shuuhei Hirose
Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, 1–3 Miyakodani, Tatara, Kyotanabe, Kyoto 610–0394, Japan; Research Fellow of Japan Society for the Promotion of Science
Tsuyoshi Waku
Laboratory for Genetic Code, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610–0394, Japan; Corresponding author
Misato Tani
Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, 1–3 Miyakodani, Tatara, Kyotanabe, Kyoto 610–0394, Japan
Haruka Masuda
Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, 1–3 Miyakodani, Tatara, Kyotanabe, Kyoto 610–0394, Japan
Keiko Endo
Institute for Advanced Biosciences, Keio University, Kakuganji, Tsuruoka 997-0052, Japan
Sanae Ashitani
Institute for Advanced Biosciences, Keio University, Kakuganji, Tsuruoka 997-0052, Japan
Iori Aketa
Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, 1–3 Miyakodani, Tatara, Kyotanabe, Kyoto 610–0394, Japan
Hina Kitano
Laboratory for Genetic Code, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610–0394, Japan
Sota Nakada
Laboratory for Genetic Code, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610–0394, Japan
Ayaka Wada
Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, 1–3 Miyakodani, Tatara, Kyotanabe, Kyoto 610–0394, Japan
Atsushi Hatanaka
Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, 1–3 Miyakodani, Tatara, Kyotanabe, Kyoto 610–0394, Japan
Tsuyoshi Osawa
Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
Tomoyoshi Soga
Institute for Advanced Biosciences, Keio University, Kakuganji, Tsuruoka 997-0052, Japan
Akira Kobayashi
Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, 1–3 Miyakodani, Tatara, Kyotanabe, Kyoto 610–0394, Japan; Laboratory for Genetic Code, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610–0394, Japan; Corresponding author
Summary: 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.
