The AMPK/TAK1/NF-kB signaling axis is indispensable for modulating ovarian cancer cell metabolism and peritoneal metastases

Abstract

Ovarian cancer is an intra-abdominal tumor and metastatic dissemination is usually confined in the peritoneal cavity accompanied with the presence of ascites. Malignant ascites provides a key source of soluble growth factors, chemokines and fatty acids determining the morbidity and mortality of ovarian cancer patients. However, the underlying molecular mechanisms for the dynamic interplay of the ascites microenvironment and ovarian cancer cells in terms of cell metabolism and altered oncogenic signalings in sustaining metastatic progression remains unknown. Here we report that the ovarian cancer cells in ascites microenvironment exhibit lipid metabolism for energy production for metastatic progression by modulating of the AMPK activities in lipogenesis and oncogenic signalings; AMPK/mTOR and TAK1/NFkB signaling axis. Omental metastasis is one of the preferential routes in peritoneal metastases of ovarian cancers and the omentum is usually removed by omentectomy. By mimicking the ascites microenvironement, an omental explant culture system (OCM) was established and ovarian cancer cells demonstrated a significant increase in cell growth, cell migration and invasion when co-cultured in this system. Biochemical analyses proved that ovarian cancer cells displayed an increased rate of lipid synthesis and ATP content when cultured in OCM. This was supported by the metabolic reprogramming from the use of aerobic glycolysis to lipid metabolism via AMPK/ACC signaling mediated lipogenesis. Intriguingly, the activated AMPK activity is quickly reduced by the high ATP production in comparison of the ACC activity in ovarian cancer cells. The reduced AMPK activity was accompanied with not only enhanced mTOR activity but also increased TAK1/NFkB signaling in ovarian cancer cells upon treatment of OCM for a longer time. Noticeably, co-treatment of TAK1 activator, PGE2, nor TAK1 specific inhibitor, (5Z)-7-Oxozeaenol (5ZO) and knockdown of TAK1, could not alter the AMPK activity. In contrast, knockdown of AMPKa1 or activating AMPK by co-treatment of metformin could significantly alter TAK1/NFkB signaling, suggesting that AMPK acts as the upstream effector of TAK1/ NFkB signaling in ovarian cancer cells. Therefore, knockdown of AMPKa1 could enhance, while co-treatment of metformin or TAK1 inhibitor 5ZO could inhibit OCM-mediated cell growth, cell migration and invasion, ex vivo omental metastasis and in vivo dissemination of ovarian cancer cells. Taken together, our findings suggest that the metastatic ovarian cancer cells utilize fatty acids as energy fuel through AMPK mediated ACC-lipogenesis, mTOR and TAK1/NF-kB signaling axis in ovarian cancer development and metastasis.