Department of Glyco-Oncology and Medical Biochemistry, Research Institute, Osaka International Cancer Institute, Osaka, Japan
Yu Mizote
Department of Cancer Drug Discovery and Development, Research Institute, Osaka International Cancer Institute, Osaka, Japan
Takehiro Suzuki
Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Saitama, Japan
Akiyoshi Hirayama
Institute for Advanced Biosciences, Keio University, Yamagata, Japan; Systems Biology Program, Graduate School of Media and Governance, Keio University, Kanagawa, Japan
Satsuki Ikeda
Institute for Advanced Biosciences, Keio University, Yamagata, Japan
Mikako Nishida
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Toru Hiratsuka
Department of Oncogenesis and Growth Regulation, Research Institute, Osaka International Cancer Institute, Osaka, Japan
Ayaka Ueda
Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, Osaka, Japan
Yusuke Imagawa
Department of Oncogenesis and Growth Regulation, Research Institute, Osaka International Cancer Institute, Osaka, Japan
Kento Maeda
Department of Glyco-Oncology and Medical Biochemistry, Research Institute, Osaka International Cancer Institute, Osaka, Japan
Yuki Ohkawa
Department of Glyco-Oncology and Medical Biochemistry, Research Institute, Osaka International Cancer Institute, Osaka, Japan
Junko Murai
Institute for Advanced Biosciences, Keio University, Yamagata, Japan; Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Ehime, Japan; Department of Biochemistry and Molecular Genetics, Graduate School of Medicine, Ehime University, Ehime, Japan
Hudson H Freeze
Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
Eiji Miyoshi
Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, Osaka, Japan
Shigeki Higashiyama
Department of Oncogenesis and Growth Regulation, Research Institute, Osaka International Cancer Institute, Osaka, Japan; Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Ehime, Japan; Department of Biochemistry and Molecular Genetics, Graduate School of Medicine, Ehime University, Ehime, Japan
Heiichiro Udono
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Saitama, Japan
Hideaki Tahara
Department of Cancer Drug Discovery and Development, Research Institute, Osaka International Cancer Institute, Osaka, Japan; Project Division of Cancer Biomolecular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Naoyuki Taniguchi
Department of Glyco-Oncology and Medical Biochemistry, Research Institute, Osaka International Cancer Institute, Osaka, Japan
Mannose has anticancer activity that inhibits cell proliferation and enhances the efficacy of chemotherapy. How mannose exerts its anticancer activity, however, remains poorly understood. Here, using genetically engineered human cancer cells that permit the precise control of mannose metabolic flux, we demonstrate that the large influx of mannose exceeding its metabolic capacity induced metabolic remodeling, leading to the generation of slow-cycling cells with limited deoxyribonucleoside triphosphates (dNTPs). This metabolic remodeling impaired dormant origin firing required to rescue stalled forks by cisplatin, thus exacerbating replication stress. Importantly, pharmacological inhibition of de novo dNTP biosynthesis was sufficient to retard cell cycle progression, sensitize cells to cisplatin, and inhibit dormant origin firing, suggesting dNTP loss-induced genomic instability as a central mechanism for the anticancer activity of mannose.
