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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  ;  Seungbin Cha  ;  Sang Bum Kim  ;  Hakhyun Kim  ;  Seonghwi Choi  ;  Sejin Oh  ;  Minseo Kim  ;  Yunji Lee  ;  Gino Kwon  ;  Jooyoung Lee  ;  Joo-Youn Lee  ;  Gyoonhee Han  ;  Hyun Seok Kim 
 BMB REPORTS, Vol.55(12) : 645-650, 2022-12 
Journal Title
Issue Date
Antineoplastic Agents* / pharmacology ; Antineoplastic Agents* / therapeutic use ; Apoptosis ; Cell Line, Tumor ; Epithelial-Mesenchymal Transition ; Humans ; Stomach Neoplasms* / drug therapy ; Stomach Neoplasms* / genetics ; Stomach Neoplasms* / pathology
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 chemoresistance 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 smallmolecule 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. [BMB Reports 2022; 55(12): 645-650].
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Sang Bum(김상범) ORCID logo https://orcid.org/0000-0001-5965-3354
Kim, Hyun Seok(김현석) ORCID logo https://orcid.org/0000-0003-4498-8690
Lee, Joo Young(이주영)
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