Lysine-arginine imbalance overcomes therapeutic tolerance governed by the transcription factor E3-lysosome axis in glioblastoma
Recent advances in cancer therapy have underscored the importance of targeting specific metabolic pathways. In this study, we propose a precision nutrition approach aimed at lysosomal function in glioblastoma multiforme (GBM). Using patient-derived GBM cells, we identify lysosomal activity as a unique metabolic biomarker of tumorigenesis, controlling the efficacy of temozolomide (TMZ), a standard GBM therapy. Employing combined analyses of clinical patient samples and xenograft models, we further elucidate the pivotal role of Transcription Factor Binding To IGHM Enhancer 3 (TFE3), a master regulator of lysosomal biogenesis, in modulating malignant properties, particularly TMZ tolerance, by regulating peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α)-mediated mitochondrial activity. Notably, we find that lysine protects GBM cells from lysosomal stress by counteracting arginine's effects on nitric oxide production. The lysine restriction mimetic, homoarginine administration, significantly enhances the efficacy of anticancer therapies through lysosomal dysfunction. This study underscores the critical role of lysosomal function modulated by amino acid metabolism in GBM pathogenesis and treatment.
Authors
- Atsuko Kasahara (ORCID: https://orcid.org/0000-0002-1171-7600)
- Yongwei Jing (ORCID: https://orcid.org/0009-0004-8539-6282)
- Shinichi Hashimoto (ORCID: https://orcid.org/0000-0002-1223-2349)
- Meiqi Zhou (ORCID: https://orcid.org/0000-0002-1224-2694)
- Mahmoud I. Shoulkamy (ORCID: https://orcid.org/0000-0002-4736-1212)
- Kenta Kurayoshi (ORCID: https://orcid.org/0009-0008-8194-0489)
- Mitsutoshi Nakada (ORCID: https://orcid.org/0000-0001-9419-6101)
- Tomoyoshi Soga (ORCID: https://orcid.org/0000-0001-9502-2509)
- Sadahiro Iwabuchi (ORCID: https://orcid.org/0000-0003-0434-3054)
- Cong Quang Vu (ORCID: https://orcid.org/0000-0001-7444-9060)
- Tomoki Todo (ORCID: https://orcid.org/0000-0003-0523-8010)
- Hemragul Sabit
- Thi Ha Vu (ORCID: https://orcid.org/0000-0002-9866-5689)
- Masahiko Kobayashi (ORCID: https://orcid.org/0000-0001-6539-7326)
- Masaya Ueno (ORCID: https://orcid.org/0000-0001-9177-8640)
- Yu‐Hang Yan
- Satoshi Arai (ORCID: https://orcid.org/0000-0003-4807-8248)
- Atsushi Hirao (ORCID: https://orcid.org/0000-0001-7818-8240)
- Xi Chen (ORCID: https://orcid.org/0000-0001-8473-7920)
- Hiroshi Arakawa
- Yuko Tadokoro
Institutions
- Kanazawa University (JP)
- Kanazawa Medical University (JP)
- Hanoi Medical University (VN)
- Wakayama Medical University (JP)
- Keio University (JP)
- Life Science Institute (JP)
- The University of Tokyo (JP)
- Minia University (EG)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1038/s41467-025-56946-z
- Citations
- 6
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 8.13
Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science