Metformin inhibits growth of human non-small cell lung cancer cells via liver kinase B-1-independent activation of adenosine monophosphate-activated protein kinase
| Autor: | Zhiyan Liu, Jiequn Ma, Qianqian Guo, Mengjie Liu, Xuan Liang, Chengcheng Yang, Lili Han, Lili Jiang, Kejun Nan |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Small interfering RNA endocrine system diseases Antineoplastic Agents Apoptosis AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Biochemistry 03 medical and health sciences 0302 clinical medicine AMP-Activated Protein Kinase Kinases AMP-activated protein kinase Carcinoma Non-Small-Cell Lung Cell Line Tumor Genetics medicine Humans Protein kinase A Molecular Biology non-small cell lung cancer mammalian target of rapamycin Cell Proliferation biology Cell growth Cell Cycle AMPK Articles Cell cycle Molecular biology Metformin liver kinase B1 Enzyme Activation 030104 developmental biology Liver Oncology 030220 oncology & carcinogenesis adenosine monophosphate-activated protein kinase biology.protein Cancer research Molecular Medicine Signal transduction Signal Transduction medicine.drug |
| Zdroj: | Molecular Medicine Reports |
| ISSN: | 1791-3004 1791-2997 |
| DOI: | 10.3892/mmr.2016.4830 |
| Popis: | Metformin, the most widely administered oral anti‑diabetic therapeutic agent, exerts its glucose-lowering effect predominantly via liver kinase B1 (LKB1)-dependent activation of adenosine monophosphate-activated protein kinase (AMPK). Accumulating evidence has demonstrated that metformin possesses potential antitumor effects. However, whether the antitumor effect of metformin is via the LKB1/AMPK signaling pathway remains to be determined. In the current study, the effects of metformin on proliferation, cell cycle progression, and apoptosis of human non‑small cell lung cancer (NSCLC) H460 (LKB1‑null) and H1299 (LKB1‑positive) cells were assessed, and the role of LKB1/AMPK signaling in the anti‑growth effects of metformin were investigated. Cell viability was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle distribution and apoptosis were assessed by flow cytometry, and protein expression levels were measured by western blotting. Metformin inhibited proliferation, induced significant cell cycle arrest at the G0‑G1 phase and increased apoptosis in NSCLC cells in a time- and concentration-dependent manner, regardless of the level of LKB1 protein expression. Furthermore, knockdown of LKB1 with short hairpin RNA (shRNA) did not affect the antiproliferative effect of metformin in the H1299 cells. Metformin stimulated AMPK phosphorylation and subsequently suppressed the phosphorylation of mammalian target of rapamycin and its downstream effector, 70‑kDa ribosomal protein S6 kinase in the two cell lines. These effects were abrogated by silencing AMPK with small interfering RNA (siRNA). In addition, knockdown of AMPK with siRNA inhibited the effect of metformin on cell proliferation in the two cell lines. These results provide evidence that the growth inhibition of metformin in NSCLC cells is mediated by LKB1‑independent activation of AMPK, indicating that metformin may be a potential therapeutic agent for the treatment of human NSCLC. |
| Databáze: | OpenAIRE |
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