MS TITLE: Activation of AMP-activated Protein Kinase Attenuates Hepatocellular Carcinoma Cell Adhesion Stimulated by Adipokine Resistin AUTHORS:

Background: Resistin, a recently discovered adipocyte-secreting adipokine, may play critical role in modulating cancer pathogenesisestablish a new association between obesity and hepatocellular carcinoma (HCC) metastasis. The aim of this study was to investigate the effects of resistin on HCC adhesion to the endothelium, and the mechanism underlying these resistin effects. Methods: Human SK-Hep1 cells were used to study the effect of resistin on intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions as well as NF-κB activation, and hence cell adhesion to human umbilical vein endothelial cells (HUVECs). 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an AMP-activated protein kinase (AMPK) activator, was used to determine the regulatory role of AMPK on HCC adhesion to the endothelium in regard to the resistin effects. Results: Treatment with resistin increased the adhesion of SK-Hep1 cells to HUVECs and concomitantly induced NF-κB activation, as well as ICAM-1 and VCAM-1 expressions in SK-Hep1 cells. Using specific blocking antibodies and siRNAs, we found that resistin-induced SK-Hep1 cell adhesion to HUVECs was through Inhibition of NF-κB-regulated, ICAM-1 and VCAM-1 expressions by using blocking neutralizing antibodies and/or specific siRNAs decreased SK-Hep1 cell adhesion to HUVECs. Moreover, treatment with AICAR demonstrated that AMPK activation in SK-Hep1 cells significantly attenuates the resistin effect on SK-Hep1 cell adhesion to HUVECs. Conclusions: These results clarify that the role of resistin role in inducing HCC adhesion to the endothelium increases SK-Hep1 cell adhesion to HUVECs and demonstrate the inhibitory effect of AMPK activation onunder the resistin stimulation.;