Metformin inhibits P-glycoprotein expression via the NF-kappa B pathway and CRE transcriptional activity through AMPK activation

Title
Metformin inhibits P-glycoprotein expression via the NF-kappa B pathway and CRE transcriptional activity through AMPK activation
Author(s)
김형균[김형균]트란 티 히엔[트란 티 히엔]한은희[한은희]황용필[황용필]최재호[최재호]강건욱[강건욱]권광일[권광일]김봉희[김봉희]김상겸[김상겸]송계용[송계용]정태천정혜광[정혜광]
Keywords
BACTERIAL TRANSPORT PROTEINS; ANTIDIABETIC DRUG METFORMIN; MULTIDRUG-RESISTANCE GENE; BREAST-CANCER-CELLS; PHOSPHOINOSITIDE 3-KINASE; KINASE ACTIVATION; ENDOTHELIAL-CELLS; MDR1B EXPRESSION; PHOSPHORYLATION; INDUCTION
Issue Date
201103
Publisher
WILEY-BLACKWELL
Citation
BRITISH JOURNAL OF PHARMACOLOGY, v.162, no.5, pp.1096 - 1108
Abstract
BACKGROUND AND PURPOSE The expression of P-glycoprotein (P-gp), encoded by the multidrug resistance 1 (MDR1) gene, is associated with the emergence of the MDR phenotype in cancer cells. We investigated whether metformin (1,1-dimethylbiguanide hydrochloride) down-regulates MDR1 expression in MCF-7/adriamycin (MCF-7/adr) cells. EXPERIMENTAL APPROACH MCF-7 and MCF-7/adr cells were incubated with metformin and changes in P-gp expression were determined at the mRNA, protein and functional level. Transient transfection assays were performed to assess its gene promoter activities, and immunoblot analysis to study its molecular mechanisms of action. KEY RESULTS Metformin significantly inhibited MDR1 expression by blocking MDR1 gene transcription. Metformin also significantly increased the intracellular accumulation of the fluorescent P-gp substrate rhodamine-123. Nuclear factor-kappa B (NF-kappa B) activity and the level of I kappa B degradation were reduced by metformin treatment. Moreover, transduction of MCF-7/adr cells with the p65 subunit of NF-kappa B induced MDR1 promoter activity and expression, and this effect was attenuated by metformin. The suppression of MDR1 promoter activity and protein expression was mediated through metformin-induced activation of AMP-activated protein kinase (AMPK). Small interfering RNA methods confirmed that reduction of AMPK levels attenuates the inhibition of MDR1 activation associated with metformin exposure. Furthermore, the inhibitory effects of metformin on MDR1 expression and cAMP-responsive element binding protein (CREB) phosphorylation were reversed by overexpression of a dominant-negative mutant of AMPK. CONCLUSIONS AND IMPLICATIONS These results suggest that metformin activates AMPK and suppresses MDR1 expression in MCF-7/adr cells by inhibiting the activation of NF-kappa B and CREB. This study reveals a novel function of metformin as an anticancer agent.
URI
http://hdl.handle.net/YU.REPOSITORY/25557http://dx.doi.org/10.1111/j.1476-5381.2010.01101.x
ISSN
0007-1188
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약학대학 > 약학부 > Articles
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