Selective cytotoxicity of a novel mitochondrial complex I inhibitor, YK-135, against EMT-subtype gastric cancer cell lines due to impaired glycolytic capacity

• Published in: BMB reports 2022-12, Vol.55 (12), p.645-650
• Main Authors: 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
• Format: Article
• Language: Korean
• Subjects: EMT; Gastric cancer; Glycolytic capacity; Mitochondrial complex I; OXPHOS
• ISSN: 1976-6696; 1976-670X

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. [BMB Reports 2022; 55(12): 645-650]