Metformin induces cytotoxicity by down-regulating thymidine phosphorylase and excision repair cross-complementation 1 expression in non-small cell lung cancer cells.
Basic Clin Pharmacol Toxicol
; 113(1): 56-65, 2013 Jul.
Article
em En
| MEDLINE
| ID: mdl-23362830
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Timidina Fosforilase
/
Proteínas de Ligação a DNA
/
Endonucleases
/
Hipoglicemiantes
/
Metformina
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Basic Clin Pharmacol Toxicol
Assunto da revista:
FARMACOLOGIA
/
TOXICOLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Taiwan