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When \u03b2\u2010catenin: a component of the Wnt pathway, is mutated into an active form, cell growth signaling is hyperactive and drives oncogenesis. As \u03b2\u2010catenin is mutated in a wide variety of tumors, including up to 10% of all sporadic colon carcinomas and 20% of hepatocellular carcinomas, it has been considered a promising target for therapeutic interventions. Therefore, we screened an in\u2010house natural product library for compounds that exhibited synthetic lethality towards \u03b2\u2010catenin mutations and isolated nonactin, an antibiotic mitochondrial uncoupler, as a hit compound. Nonactin, as well as other mitochondrial uncouplers, induced apoptosis selectively in \u03b2\u2010catenin mutated tumor cells. Significant tumor regression was observed in the \u03b2\u2010catenin mutant <jats:styled-content style=\"fixed-case\">HCT<\/jats:styled-content> 116 xenograft model, but not in the \u03b2\u2010catenin wild type A375 xenograft model, in response to daily administration of nonactin <jats:italic>in vivo<\/jats:italic>. Furthermore, we found that expression of an active mutant form of \u03b2\u2010catenin induced a decrease in the glycolysis rate. Taken together, our results demonstrate that tumor cells with mutated \u03b2\u2010catenin depend on mitochondrial oxidative phosphorylation for survival. Therefore, they undergo apoptosis in response to mitochondrial dysfunction following the addition of mitochondrial uncouplers, such as nonactin. These results suggest that targeting mitochondria is a potential chemotherapeutic strategy for tumor cells that harbor \u03b2\u2010catenin mutations.<\/jats:p>","DOI":"10.1111\/cas.13172","type":"journal-article","created":{"date-parts":[[2017,1,20]],"date-time":"2017-01-20T21:51:18Z","timestamp":1484949078000},"page":"772-784","source":"Crossref","is-referenced-by-count":23,"title":["Mitochondrial uncoupler exerts a synthetic lethal effect against \u03b2\u2010catenin mutant tumor cells"],"prefix":"10.1111","volume":"108","author":[{"given":"Yuki","family":"Shikata","sequence":"first","affiliation":[{"name":"Department of Biosciences and Informatics Faculty of Science and Technology Keio University Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Kiga","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Informatics Faculty of Science and Technology Keio University Yokohama 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