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Metformin Induces Cytotoxicity by Down‐Regulating Thymidine Phosphorylase and Excision Repair Cross‐Complementation 1 Expression in Non‐Small Cell Lung Cancer Cells
Author(s) -
Ko JenChung,
Huang YuChing,
Chen HuangJen,
Tseng ShengChieh,
Chiu HsienChun,
Wo TingYu,
Huang YiJhen,
Weng ShaoHsing,
Chiou Robin Y. Y.,
Lin YunWei
Publication year - 2013
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12052
Subject(s) - ercc1 , cytotoxicity , metformin , thymidine phosphorylase , cancer research , cancer cell , cell growth , transfection , biology , lung cancer , cell culture , cancer , microbiology and biotechnology , chemistry , medicine , endocrinology , biochemistry , in vitro , nucleotide excision repair , dna repair , gene , insulin , genetics
Metformin 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 ( ERCC 1) 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 ERCC 1 expression in metformin‐induced cytotoxicity. Metformin treatment decreased cellular TP and ERCC 1 protein and mRNA levels by down‐regulating phosphorylated MEK 1/2‐ ERK 1/2 protein levels in a dose‐ and time‐dependent manner. The enforced expression of the constitutively active MEK 1 ( MEK1‐CA ) vectors significantly restored cellular TP and ERCC 1 protein levels and cell viability. Specific inhibition of TP and ERCC 1 expression by siRNA enhanced the metformin‐induced cytotoxicity and growth inhibition. Arachidin‐1, an antioxidant stilbenoid, further decreased TP and ERCC 1 expression and augmented metformin's cytotoxic effect, which was abrogated in lung cancer cells transfected with MEK 1/2‐ CA expression vector. In conclusion, metformin induces cytotoxicity by down‐regulating TP and ERCC 1 expression in NSCLC cells.