Metformin induces cytotoxicity by down-regulating thymidine phosphorylase and excision repair cross-complementation 1 expression in non-small cell lung cancer cells.
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 (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.
Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Taiwan.
Jen-Chung
JC
Ko
Yu-Ching
YC
Huang
Huang-Jen
HJ
Chen
Sheng-Chieh
SC
Tseng
Hsien-Chun
HC
Chiu
Ting-Yu
TY
Wo
Yi-Jhen
YJ
Huang
Shao-Hsing
SH
Weng
Robin Y Y
RY
Chiou
Yun-Wei
YW
Lin
D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004720:Endonucleases / Q000096:biosynthesis*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology*; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013939:Thymidine Phosphorylase / Q000096:biosynthesis*; D013997:Time Factors
D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D008687:Metformin; D013939:Thymidine Phosphorylase; D048369:MAP Kinase Kinase 1; C071447:ERCC1 protein, human; D004720:Endonucleases