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KMID : 0624620220550120645
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BMB Reports
2022 Volume.55 No. 12 p.645 ~ p.650
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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
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Sung Yeo-Jin
Cha Seung-Bin
Kim Sang-Bum
Kim Hak-Hyun
Choi Seong-Hwi
Oh Se-Jin
Kim Min-Seo
Lee Yun-Ji
Kwon Gi-No
Lee Joo-Young
Lee Joo-Youn
Han Gyoon-hee
Kim Hyun-Seok
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Abstract
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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 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.
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KEYWORD
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EMT, Gastric cancer, Glycolytic capacity, Mitochondrial complex I, OXPHOS
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