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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Epithelial-to-mesenchymal transition (EMT)-subtype gastric cancershave the worst prognosis due to their higher recurrence rate,higher probability of developing metastases and higher chemoresistancecompared to those of other molecular subtypes. Pharmacologicallyactionable somatic mutations are rarely found inEMT-subtype gastric cancers, limiting the utility of targeted therapies. Here, we conducted a high-throughput chemical screenusing 37 gastric cancer cell lines and 48,467 synthetic smallmoleculecompounds. We identified YK-135, a small-moleculecompound that showed higher cytotoxicity toward EMT-subtypegastric cancer cell lines than toward non-EMT-subtype gastriccancer cell lines. YK-135 exerts its cytotoxic effects by inhibitingmitochondrial complex I activity and inducing AMP-activatedprotein kinase (AMPK)-mediated apoptosis. We found that thelower glycolytic capacity of the EMT-subtype gastric cancer cellsconfers synthetic lethality to the inhibition of mitochondrialcomplex I, possibly by failing to maintain energy homeostasis. Other well-known mitochondrial complex I inhibitors (e.g., rotenoneand phenformin) mimic the efficacy of YK-135, supportingour results. These findings highlight mitochondrial complex Iinhibitors as promising therapeutic agents for EMT-subtype gastriccancers and YK-135 as a novel chemical scaffold for further drugdevelopment.
Abstract
Epithelial-to-mesenchymal transition (EMT)-subtype gastric cancershave the worst prognosis due to their higher recurrence rate,higher probability of developing metastases and higher chemoresistancecompared to those of other molecular subtypes. Pharmacologicallyactionable somatic mutations are rarely found inEMT-subtype gastric cancers, limiting the utility of targeted therapies. Here, we conducted a high-throughput chemical screenusing 37 gastric cancer cell lines and 48,467 synthetic smallmoleculecompounds. We identified YK-135, a small-moleculecompound that showed higher cytotoxicity toward EMT-subtypegastric cancer cell lines than toward non-EMT-subtype gastriccancer cell lines. YK-135 exerts its cytotoxic effects by inhibitingmitochondrial complex I activity and inducing AMP-activatedprotein kinase (AMPK)-mediated apoptosis. We found that thelower glycolytic capacity of the EMT-subtype gastric cancer cellsconfers synthetic lethality to the inhibition of mitochondrialcomplex I, possibly by failing to maintain energy homeostasis. Other well-known mitochondrial complex I inhibitors (e.g., rotenoneand phenformin) mimic the efficacy of YK-135, supportingour results. These findings highlight mitochondrial complex Iinhibitors as promising therapeutic agents for EMT-subtype gastriccancers and YK-135 as a novel chemical scaffold for further drugdevelopment.
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