title: Metformin inhibits growth of human non-small cell lung cancer cells via liver kinase B-1-independent activation of adenosine monophosphate-activated protein kinase.
abstract: 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.
authors: Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University Medical College, Xi'an, Shaanxi 710061, P.R. China.
authors: Qianqian
authors: Q
authors: Guo
authors: Department of Respiration, Xi'an Central Hospital, Xi'an, Shaanxi 710003, P.R. China.
authors: Zhiyan
authors: Z
authors: Liu
authors: Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University Medical College, Xi'an, Shaanxi 710061, P.R. China.
authors: Lili
authors: L
authors: Jiang
authors: Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University Medical College, Xi'an, Shaanxi 710061, P.R. China.
authors: Mengjie
authors: M
authors: Liu
authors: Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University Medical College, Xi'an, Shaanxi 710061, P.R. China.
authors: Jiequn
authors: J
authors: Ma
authors: Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University Medical College, Xi'an, Shaanxi 710061, P.R. China.
authors: Chengcheng
authors: C
authors: Yang
authors: Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University Medical College, Xi'an, Shaanxi 710061, P.R. China.
authors: Lili
authors: L
authors: Han
authors: Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University Medical College, Xi'an, Shaanxi 710061, P.R. China.
authors: Kejun
authors: K
authors: Nan
authors: Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University Medical College, Xi'an, Shaanxi 710061, P.R. China.
authors: Xuan
authors: X
authors: Liang
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000178:diet therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000201:enzymology; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases