The significance of lipid metabolism in peritoneal metastases of ovarian cancer

Abstract

Ovarian cancer is the leading cause of mortality rate of all gynecological malignancies worldwide. Ovarian cancer tends to metastasize via transcoelomic routes with the presence of ascites, which is a big reservoir containing bioactive lipids, cytokines and pro-inflammatory aggregates. Emerging evidence suggests the tumorigenic properties of ovarian cancer cells are significantly enhanced in ascites. However, the significance of the fatty acids enriched microenvironment in promoting ovarian cancer cells is still unclear. In this study, an Omental Conditioned Medium (OCM) model was established to mimic ascites microenvironment. Co-cultured ovarian cancer cells in OCM showed a significantly increase in cell proliferation, cell migration, and cell invasion, indicating ascites microenvironment provides free fatty acids for ovarian cancer cells to facilitate tumor dissemination.

Indeed, using LC-MS/MS based quantitive proteomic approach, the activity of lipid metabolism was highly activated in ovarian cancer cells when cultured in OCM. Functionally, co-culture with OCM or ascites could significantly increase the lipid droplet accumulation and energy production. While removal of lipid in OCM or ascites abrogated the increased cell growth and cell migratory/invasive capacities. As glycolysis is commonly found in cancer development, it is of interest to examine its dominancy in OCM-cocultured ovarian cancer cells. However, inhibition of glycolysis by either knockdown of glucose transporter-1 (GLUT-1) or treatment with glycolysis inhibitor (STF31) could not reduce any oncogenic increment of ovarian cancer cells. On the contrary, the depletion of Acetyl-CoA carboxylase  (ACC or ACCby shRNA approach, or pharmaceutical inhibition of FASN by orlistat significantly attenuated not only ATP generation but also all enhanced tumorigenic properties, indicating a metabolic shift of ovarian cancer cells from aerobic glycolysis to -oxidation when cultured in fatty acid-enriched microenvironment. On the other hand, the enhanced lipogenesis was proved by the upregulation of fatty acid synthase (FASN) in ovarian cancer cells, while inhibition of FASN by either shRNAi approach or FASN inhibitor remarkably inhibited the cell growth and ATP production, indicating FASN is a key enzyme for utilizing the uptake fatty acids for production of cellular blocks. Moreover, the activity of AMP-activated protein kinase (AMPK), a key sensor and regulator in energy balance, was initially activated and gradually reduced due to a negative feedback loop of high ATP production in OCM-cultured ovarian cancer cells. The reduced AMPK activity, led to the activation of mTOR and TAK1/NF-B signaling cascades, which in turn promoted cell growth and aggressiveness of ovarian cancer cells. Hence, treatment with AMPK activator and/or TAK1 inhibitor significantly impaired the OCM-mediated oncogenic augmentation of ovarian cancer cells in vitro and in vivo. While the combination of AMPK activator, TAK1 and FASN inhibitors could synergistically suppress tumor growth and metastasis.

To conclude, these findings suggest that ovarian cancer cells undergo metabolic reprogramming from glycolysis to -oxidation in the process of metastasis in ascites or fatty acid-enriched microenvironment. The enhanced lipogenesis and lipolysis plays an important role in metastatic progression of ovarian cancer. Targeting lipid metabolism at AMPK/ACC/FASN and AMPK/TAK1/NF-B signaling axis might be a promising approach to impede peritoneal metastases of ovarian cancer.