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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.

The occurrence of shallow and deep-water sedimentary facies has established the Yangtze Platform in South China as a key site for the study of Neoproterozoic ocean oxidation and Ediacaran animal evolution following the Marinoan glaciation. The Yanwutan section in Hunan Province is one of the few coherent sections on the Yangtze Platform where Ediacaran deep-water carbonate sediments (predominantly dolostones) are preserved together with organic carbon-rich shales. Here we present new major and trace element abundance data as well as Sr-, O-and C-isotope compositions of leachates from carbonates of the Doushantuo Formation. We evaluate the role of diagenetic modification of the carbonate rocks and constrain the redox evolution of Ediacaran seawater in space and time. 87 O of cap dolostones at many other sections were compromised by hydrothermal alteration. The overlying organic carbon poor micritic dolostone (unit II) shows negative Ce-anomalies that disappear towards the top of the unit. No Ce-anomalies occur in subsequent organic carbon-rich muddy dolostone units (units III to IV). These observations, enrichments in TOC that correlate with variations in redox-sensitive metals in the carbonates, negative d 13 C carb in units II to IV and the decoupling of d 13 C carb from d 13 C org argue for the existence of mostly anoxic deep-water at the Yangtze passive continental margin during the Ediacaran. The negative Ce-anomalies at the base of unit II (with negative d 13 C carb ) may reflect fluctuations towards suboxic or oxic conditions or an allochthonous origin of this unit. However, trace metal enrichments in carbonates of the same unit argue for reducing conditions in pore-water, whereas the carbonates may have preserved the REE+Y signatures inherited from suboxic-to oxic seawater. The trace element and negative d 13 C carb values in units II to IV are consistent with a stratified basin model with a large partially remineralised organic matter reservoir in anoxic bottom and pore-waters.