Targeting lipid metabolism eradicates peritoneal metastases of ovarian cancer

Abstract

Ovarian cancer is one of the deadliest women malignancies in the world. The chemoresistance accompanied with metastasis lead to high mortality of this disease. Different from other solid tumors, the advanced ovarian cancers prefer transcoelomic route in metastasis. Clinical observation indicates ovarian cancer patients with intraperitoneal metastases are closely association with poor prognosis. Emerging evidence has indicated that ascites fluids which acts as a reservoir providing plenty of growth factors, chemokines and importantly, free fatty acids etc. However, the significance of ascites microenvironment in governing ovarian cancer metastatic progression remain unclear. Herein, we report that the ascites microenvironment alters metabolism that in turn, enhances ovarian cancer cell aggressiveness. By mimicking the ascites microenvironment, we established omental conditioned medium (OCM). Ovarian cancer cells co-cultured in OCM showed enhanced ovarian cancer oncogenic capacities as observed in ascites. By RNA-Seq and proteomics analyses, we found the activities of lipid metabolism were elevated in ovarian cancer cells cultured in OCM. Depletion of Glut-1/-3/-4 by shRNAi approach or treatment of STF31, a glycolysis inhibitor, showed no or slight effect on ATP production and cell growth of ovarian cancer cells. In contrast, knockdown of Acetyl-CoA Carboxylase--α or -β (ΑCC1/2) or treatment of FASN inhibitor, Orlistat, significantly inhibited the ATP production and cell growth, suggesting ovarian cancer cells undergone a metabolic shift from aerobic glycolysis to β-oxidation when co-cultured in fatty acid enriched OCM. On the other hand, AMP-activated protein kinase (AMPK) is a key energy sensor and affects oncogenic capacities of many cancer cells. We found that its activity was induced initially for triggering fatty acid oxidation in ATP production. But the AMPK activity was gradually reduced due to the negative feedback loop of high ATP content. The lowered AMPK activity led to mTOR and TAK1/NF-κB signaling activation that result in the increased oncogenic capacities of ovarian cancer cells. Notably, inhibition of the above signaling pathways by a combined cocktails of AMPK activator, TAK1 and FASN inhibitors could remarkably impair OCM-mediated oncogenic properties of ovarian cancer cells in vitro and in vivo. Taken together, these findings suggest that the ascites microenvironment induces metabolic reprogramming for ovarian cancer cells in production of energy supporting their aggressiveness, while targeting the lipid metabolism and associated signalings could impede peritoneal metastases of ovarian cancer.