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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Selective cytotoxicity of a novel mitochondrial complex I inhibitor, YK-135, against EMT-subtype gastric cancer cell lines due to impaired glycolytic capacity

  • Yeojin, Sung (Sevrance Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Seungbin, Cha (Sevrance Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Sang Bum, Kim (Sevrance Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Hakhyun, Kim (Sevrance Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Seonghwi, Choi (Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University) ;
  • Sejin, Oh (Sevrance Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Minseo, Kim (Sevrance Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Yunji, Lee (Sevrance Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Gino, Kwon (Graduate Program for Nanomedical Science, Yonsei University) ;
  • Jooyoung, Lee (Sevrance Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Joo-Youn, Lee (Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology) ;
  • Gyoonhee, Han (Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University) ;
  • Hyun Seok, Kim (Sevrance Biomedical Research Institute, Yonsei University College of Medicine)
  • Received : 2022.09.26
  • Accepted : 2022.11.14
  • Published : 2022.12.31
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Abstract

Epithelial-to-mesenchymal transition (EMT)-subtype gastric cancers have the worst prognosis due to their higher recurrence rate, higher probability of developing metastases and higher chemo-resistance compared to those of other molecular subtypes. Pharmacologically actionable somatic mutations are rarely found in EMT-subtype gastric cancers, limiting the utility of targeted therapies. Here, we conducted a high-throughput chemical screen using 37 gastric cancer cell lines and 48,467 synthetic small-molecule compounds. We identified YK-135, a small-molecule compound that showed higher cytotoxicity toward EMT-subtype gastric cancer cell lines than toward non-EMT-subtype gastric cancer cell lines. YK-135 exerts its cytotoxic effects by inhibiting mitochondrial complex I activity and inducing AMP-activated protein kinase (AMPK)-mediated apoptosis. We found that the lower glycolytic capacity of the EMT-subtype gastric cancer cells confers synthetic lethality to the inhibition of mitochondrial complex I, possibly by failing to maintain energy homeostasis. Other well-known mitochondrial complex I inhibitors (e.g., rotenone and phenformin) mimic the efficacy of YK-135, supporting our results. These findings highlight mitochondrial complex I inhibitors as promising therapeutic agents for EMT-subtype gastric cancers and YK-135 as a novel chemical scaffold for further drug development.

Keywords

Acknowledgement

The chemical library used in this study was kindly provided by Korea Chemical Bank (http://www.chembank.org/) of Korea Research Institute of Chemical Technology (Daejeon, Korea). This study was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (HI14C1324), the National Research Foundation of Korea (NRF) (2020R1A2C3007792 and 2022R1A2B5B03001199), and the "Team Science Award" of Yonsei University College of Medicine (6-2021-0194). SBK was supported by the Brain Pool Program funded by the Ministry of Science and ICT through the NRF (2019H1D3A2A01050712). HK was supported by the Global Ph.D. Fellowship Program funded by the NRF (2019H1A2A1075632).

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