The roles of AMPK and TAK1/NF-kB signaling cascade in governing cancer cell aggressiveness in omental microenvironemnt

Abstract

INTRODUCTION: Ovarian cancer is a common and the most lethal gynecological malignancy among women. The high mortality rate of this disease is due to poor prognosis and most patients present at an advanced stage. Metastatic dissemination is a common occurrence of advanced-stage ovarian cancer and usually causes critical problem in clinical management. The omentum is an adipose tissue and ovarian cancer cells preferentially metastasize to this organ. However, the underlying molecular mechanisms for the dynamic interplay of omentum and ovarian cancer cells remain unknown. MATERIAL AND METHOD: An omental conditioned Medium (OCM) was established by collecting the surgical resected omental tissues from ovarian cancer patients and by incubating with DMEM at 38o C for 24 hours. The accumulation of lipid in ovarian cancer cells was examined by florescent staining and cellular ATP level was quantified after co-treatment with OCM. XTT cell proliferation, Transwell cell migration and invasion were performed to assess the cell growth, cell migration/invasion capacities of ovarian cancer cells in OCM. RESULT: Ovarian cancer cells co-cultured with OCM exhibited an increase in cell growth, cell migration and invasion through activation of TAK1 and NF-kB signaling activity. Intriguingly, an increase of Acetyl-CoA Carboxylase activity (phospho-ACC) was also observed, indicating the tumor cells synthesized ATP cellular energy by fatty acid oxidation for the rapid cell growth. Indeed, ovarian cancer cells cultured in OCM showed increased lipid droplets accumulation in cytosol and ATP content. However, AMPK acts as an upstream of ACC, only slight elevated initially and progressively reduced. The reduced AMPK activity led to an increase of TAK1 and NFkB signaling activities in a time dependent manner upon treatment of OCM. In contrast, co-treatment of metformin, a known AMPK activator, or knockdown of AMPKa1/2, or blocking TAK1/NFkB signaling cascade using TAK1 specific inhibitor, (5Z)-7-Oxozeaenol, could remarkably inhibit OCM-mediated cell growth, cell migration and invasion of ovarian cancer cells. CONCLUSION: These data suggest that the free fatty acid in OCM provide energy for ovarian cancer cells to support their cell growth, cell migration/invasion.