JEN-CHANG KOHuang Y.-C.Chen H.-J.Tseng S.-C.Chiu H.-C.Wo T.-Y.Huang Y.-J.Weng S.-H.Chiou R.Y.Y.Lin Y.-W.2021-10-042021-10-0420131742-7835https://www.scopus.com/inward/record.uri?eid=2-s2.0-84879234068&doi=10.1111%2fbcpt.12052&partnerID=40&md5=bd6e60837f05cd734b13a7107771a956https://scholars.lib.ntu.edu.tw/handle/123456789/583895Metformin is an antidiabetic drug recently shown to inhibit cancer cell proliferation and growth, although the involved molecular mechanisms have not been elucidated. In many cancer cells, high expression of thymidine phosphorylase (TP) and Excision repair cross-complementation 1 (ERCC1) is associated with poor prognosis. We used A549 and H1975 human non-small cell lung cancer (NSCLC) cell lines to investigate the role of TP and ERCC1 expression in metformin-induced cytotoxicity. Metformin treatment decreased cellular TP and ERCC1 protein and mRNA levels by down-regulating phosphorylated MEK1/2-ERK1/2 protein levels in a dose- and time-dependent manner. The enforced expression of the constitutively active MEK1 (MEK1-CA) vectors significantly restored cellular TP and ERCC1 protein levels and cell viability. Specific inhibition of TP and ERCC1 expression by siRNA enhanced the metformin-induced cytotoxicity and growth inhibition. Arachidin-1, an antioxidant stilbenoid, further decreased TP and ERCC1 expression and augmented metformin's cytotoxic effect, which was abrogated in lung cancer cells transfected with MEK1/2-CA expression vector. In conclusion, metformin induces cytotoxicity by down-regulating TP and ERCC1 expression in NSCLC cells. ? 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.[SDGs]SDG3arachidin 1; excision repair cross complementing protein 1; messenger RNA; metformin; mitogen activated protein kinase 1; mitogen activated protein kinase 3; proteasome; small interfering RNA; stilbene derivative; thymidine phosphorylase; ubiquitin; unclassified drug; antineoplastic activity; article; cancer cell culture; cell viability; concentration response; controlled study; cytotoxicity; down regulation; drug potentiation; enzyme inactivation; enzyme phosphorylation; gene expression; human; human cell; lung non small cell cancer; priority journal; protein expression; time; Cell Line, Tumor; DNA-Binding Proteins; Dose-Response Relationship, Drug; Endonucleases; Humans; Hypoglycemic Agents; MAP Kinase Kinase 1; MAP Kinase Signaling System; Metformin; RNA, Messenger; RNA, Small Interfering; Thymidine Phosphorylase; Time Factorsjournal article10.1111/bcpt.12052233628302-s2.0-84879234068