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However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"DDBJ\/EMBL\/GenBank\" xlink:href=\"SW1463\">SW1463<\/jats:ext-link> rectal cancer cells were more resistant to ionizing radiation and 5\u2010fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor\u2010\u03b2\/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X\u2010linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor \u03b2 receptor 2\u2010mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor\u2010\u03b2\/Smad signaling.<\/jats:p>","DOI":"10.1111\/cas.14124","type":"journal-article","created":{"date-parts":[[2019,7,6]],"date-time":"2019-07-06T15:23:50Z","timestamp":1562426630000},"page":"2834-2845","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Effects of metformin and phenformin on apoptosis and epithelial\u2010mesenchymal transition in chemoresistant rectal cancer"],"prefix":"10.1111","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0674-5110","authenticated-orcid":false,"given":"Ji\u2010Hye","family":"Park","sequence":"first","affiliation":[{"name":"Laboratory of Radiation Exposure &amp; Therapeutics National Radiation Emergency Medical Center Korea Institute of 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