Metformin inhibits growth of human non-small cell lung cancer cells via liver kinase B-1-independent activation of adenosine monophosphate-activated protein kinase

作者：Qianqian Guo, Zhiyan Liu, Lili Jiang, Mengjie Liu, Jiequn Ma, Chengcheng Yang, Lili Han, Kejun Nan, Xuan Liang · 发表于：Molecular Medicine Reports · 年份：2016 · DOI：10.3892/mmr.2016.4830 · 被引用次数：56 · 研究领域：Metabolism, Diabetes, and Cancer、PI3K/AKT/mTOR signaling in cancer、Cancer-related Molecular Pathways

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 downstre...