The significance of lipid metabolism in peritoneal metastases of ovarian cancer

Abstract

Ovarian cancer is an intra-abdominal tumor accompanied with the presence of ascites for metastatic dissemination. Ovarian cancer patients who have peritoneal metastases are usually poor in prognosis. Recent evidence has shown that malignant ascites provides a key reservoir of soluble growth factors, chemokines and fatty acids to promote ovarian cancer aggressiveness. However, how of ovarian cancer cells alter cell metabolism to adapt the ascites microenvironment and support their aggressiveness in peritoneal metastases remain unknown. In our laboratory, we have established an omental explant culture system (OCM) to imitate the ascites microenvironment for ovarian cancer cell growth. Results showed that ovarian cancer cells co-cultured in OCM exhibited increased cell growth, enhanced cell migration and invasion. Biochemical studies revealed that ovarian cancer cells co-cultured of OCM remarkably increased lipid droplets accumulation in cytosol accompanied with enhanced intracellular ATP production, while removal of lipids in OCM by Cleanascite significantly impaired the lipid droplet accumulation, ATP production and oncogenic capacities of ovarian cancer cells. Moreover, shRNAi-mediated GLUT-1 knockdown or co-treatment of glucose uptake inhibitor, STF31, could not affect the cell growth of ovarian cancer cells when cultured in OCM. In contrast, co-treatment of an inhibitor of fatty acid synthase, Orlistat, or directly knockdown of Acetyl-CoA Carboxylase 1 (ACC1) or Fatty Acid Synthase (FASN) remarkably attenuated ovarian cancer cell growth, indicating there is a metabolic shift from aerobic glycolysis to -oxidation to produce ATP cellular energy in supporting ovarian cancer cell oncogenic capacities. AMP-activated protein kinase (AMPK) is a crucial energy sensor for cells. We found that the activity of AMPK was induced initially to trigger fatty acid synthesis in ovarian cancer cells were co-cultured in lipid-enriched OCM. However, the high ATP production gradually lower the AMPK activity. The reduced AMPK activity led to increased mTOR and TAK1/NF-B signaling activities that in turn, enhances ovarian cancer aggressiveness in OCM culture. By contrary, co-treatment of pharmaceutical AMPK activator, metformin, or TAK1 inhibitor, 5ZO, significantly inhibited OCM-mediated oncogenic properties of ovarian cancer cells. Taken together, our findings suggest that the lipid-enriched microenvironment of OCM or ascetic fluid compels metabolic reprogramming in ovarian cancer cells for supporting their aggressiveness, while targeting the AMPK and TAK1/NF-B signaling axis could impede ovarian cancer peritoneal metastases.