Targeting lipid metabolism with a metabolic inhibitor cocktail eradicates peritoneal metastases of ovarian cancer

Abstract

Ovarian cancer is an intra-abdominal tumor in which the presence of ascites enables metastatic dissemination, and correlates with poor prognosis. Malignant ascites provide a key reservoir of growth factors and nutrients to augment the aggressiveness of ovarian cancer. However, the significance of metabolic alterations in ovarian cancer cells in the ascites microenvironment remains unclear. Here, we report that ovarian cancer cells exhibited increased aggressiveness in ascites microenvironment via reprogramming of lipid metabolism. Comparative proteomic analyses revealed that lipid metabolism is highly active in ovarian cancer cells when cultured in omental conditioned medium (OCM) that mimics the ascites microenvironment. Under these conditions, knockdown of Glut1, Glut3 or Glut4, or treatment with a glycolysis inhibitor (STF31) did not alter cell growth. By contrast, depletion of acetyl-CoA carboxylase-1 or -2 (ACC1/ACC2) or fatty acid synthase (FASN), or treatment with the FASN inhibitor orlistat remarkably attenuated ATP production and cell growth, indicating a metabolic shift from aerobic glycolysis to β-oxidation in ovarian cancer cells. This shift was evidenced by increases in lipogenesis and fatty acid β-oxidation to generate ATP for supporting oncogenic capacities of ovarian cancer cells. However, the activity of AMP-activated protein kinase (AMPK), a crucial energy sensor, was initially induced to trigger fatty acid oxidation but was then gradually reduced due to the feedback effect of high ATP production. The reduced AMPK activity led to significant activation of mTOR and TAK1/NF-κB signaling, which in turn, enhanced the growth of ovarian cancer cells. Notably, combined treatment of AMPK activators, TAK1 inhibitor and FASN inhibitor could significantly impair OCM-mediated oncogenic augmentation of ovarian cancer cells in vitro and in vivo. Collectively, our findings suggest that the ascites microenvironment compels metabolic reprogramming in ovarian cancer cells to support their aggressiveness, while targeting lipid metabolism and TAK1/NF-κB signaling axis could impede ovarian cancer peritoneal metastases.