AMP-activated protein kinase (AMPK) is a conserved sensor of cellular energy change and is activated by increased AMP/ATP and/or ADP/ATP ratios. AMPK maintains the energy balance by decreasing the ATP-consuming processes such as transcription of synthetic fat genes and rRNA, the translation of ribosomal proteins, synthesis of cholesterol and fatty acid, while the metabolic pathways such as glucose and fatty transport, fatty acid oxidation, autophagy, mitochondrial synthesis and oxidative metabolism are increased to preserve ATP during energy deficiency. Recent advance has demonstrated that AMPK activity has a close association with the initiation and progression in various cancers. Here we review the mechanisms that AMPK controls energy metabolism through regulating ATP synthesis and consumption, and further discuss the deregulation of AMPK in cancers.

BackgroundHelicobacter pylori (H. pylori) delivers oncoprotein CagA into gastric epithelial cells via the T4SS and drives activation of multiple oncogenic signalling pathways. YAP, a core effector of the Hippo tumour suppressor pathway, is frequently overexpressed in human cancers, suggesting its potential tumor-promoting role. Although CagA is a casual factor in H. pylori induced gastric carcinogenesis, the link between CagA and YAP pathway has not been identified. In this work, we investigated the regulation of oncogenic YAP pathway by H. pylori CagA.MethodsExpression of YAP and E-cadherin protein in human gastric biopsies were assessed by immunohistochemistry. H. pylori PMSS1 cagA− isogenic mutant strains were generated. Gastric epithelial cells were co-cultured with H. pylori wild-type cagA+ strains or isogenic mutants and were also treated by recombinant CagA expression. Immunofluorescence was performed for YAP localization. Immunoblot and quantitative PCR were performed for examining levels of YAP, downstream effectors and markers of epithelial-mesenchymal transition. Verteporfin and siRNA silencing were used to inhibit YAP activity.ResultsYAP is significantly upregulated in human gastric carcinogenesis. We generated PMSS1 CagA isogenic mutant strains with chloramphenicol resistance successfully. Our analysis indicated that H. pylori infection induced YAP and downstream effectors in gastric epithelial cells. Importantly, knockout of CagA in 7.13 and PMSS1 strains reduced the expression of YAP by H. pylori infection. Moreover, Inhibition of YAP suppressed H. pylori infection-induced Epithelial-mesenchymal transition (EMT).ConclusionOur results indicated that H. pylori CagA as a pathogenic protein promotes oncogenic YAP pathway, which contributes to EMT and gastric tumorigenesis. This study provided a novel mechanistic insight into why cagA+ H. pylori infection is associated with a higher risk for the development of gastric cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0962-5) contains supplementary material, which is available to authorized users.

AMP-activated protein kinase (AMPK), an important downstream effector of the tumor suppressor liver kinase 1 (LKB1) and pharmacologic target of metformin, is well known to exert a preventive and inhibitory effect on tumorigenesis; however, its role in cancer progression and metastasis has not been well characterized. The present study investigates the potential roles of AMPK in inhibiting cancer-cell migration and epithelialto-mesenchymal transition (EMT) by regulating the canonical transforming growth factor b (TGF-b) signaling pathway, an important promoting factor for cancer progression. Our results showed that activation of AMPK by metformin inhibited TGF-binduced Smad2/3 phosphorylation in cancer cells in a dosedependent manner. The effect of metformin is dependent on the presence of LKB1. A similar effect was obtained by expressing a constitutive active mutant of AMPKa1 subunit, whereas the expression of a dominant negative mutant of AMPKa1 or ablation of AMPKa subunits greatly enhanced TGF-b stimulation of Smad2/3 phosphorylation. As a consequence, expression of genes downstream of Smad2/3, including plasminogen activator inhibitor-1, fibronectin, and connective tissue growth factor, was suppressed by metformin in a LKB1-dependent fashion. In addition, metformin blocked TGF-b-induced inteleukin-6 expression through both LKB1-dependent and -independent mechanisms. Our results also indicate that activation of LKB1/AMPK inhibits TGF-b-stimulated cancer cell migration. Finally, TGF-b induction of EMT was inhibited by phenformin and enhanced by knockdown of LKB1 expression with shRNA. Together, our data suggest that AMPK could be a drug target for controlling cancer progression and metastasis.

Metformin has been used as a glucose lowering drug for several centuries and is now a first-line drug for type 2 diabetes mellitus (T2DM). Since the discovery that it activates AMP-activated protein kinase (AMPK) and reduces risk of cancer, metformin has drawn great attentions. Another drug, berberine, extracted from berberis vulgaris L. (root), was an ancient herbal medicine in treating diarrhea. Ongoing experimental and clinical studies have illuminated great potential of berberine in regulation of glucose and lipid homeostasis, cancer growth and inflammation. Furthermore, the lipid lowering effect of berberine is comparable to those conventional lipid drugs but with low toxicity. Therefore, it is right time to transform beneficial effects of berberine into therapeutic practice. Metformin and berberine share many features in actions despite different structure and both could be excellent drugs in treating T2DM, obesity, cardiac diseases, tumour, as well as inflammation. Since these disorders are often connected and comprise common pathogenic factors that could be targeted by the two drugs, understanding their actions can give us rationale for expansion of their clinical uses.