The functional roles of SCD1/FADS2 lipid desaturases in modulating lipid metabolic activities and redox-driven ferroptosis in ascites-derived ovarian cancer cells

Abstract

Epithelial ovarian cancer (EOC) is one of the most lethal female malignancies. The high mortality rate of this disease is due to the lack of reliable biomarkers, leading to most patients being diagnosed at advanced stages, along with widespread cancer cells, acquired chemoresistance, and high recurrence rates. Similar to other cancers, metastasis is the main reason for cancer-related death. Clinical observation has revealed that peritoneal metastasis in EOC patients is usually associated with platinum-resistance, high recurrence rates, and poor overall prognosis. Indeed, mounting evidence has suggested that the malignant ascites functions as a reservoir providing nutrients, chemokines, and growth factors that promote tumor aggression and progression. However, the underlying molecular mechanisms of the ascites microenvironment facilitating cancer metastatic progression of EOC remain obscure. Our recent study has reported that the fatty acid-enriched ascites enforced ovarian cancer cells to undergo metabolic reprogramming through utilizing lipid metabolism for supporting tumor aggressiveness. This study further provided evidence showing that the ascites-derived ovarian cancer cells upregulated lipid desaturases such as Stearoyl-CoA desaturase-1 (SCD1) and Acyl-CoA 6-desaturase (FADS2) in mediating lipid metabolic activities and tumor aggressiveness. Consistent with clinical data from The Cancer Genome Atlas (TCGA), the upregulated SCD1 and FADS2 were positively correlated with tumor grade, recurrence rate, poor survival rate, and cisplatin-resistance of EOC. Studies using lipidomic analysis suggested that the elevation of poly- and mono-unsaturated fatty acids (UFAs) attributed to the upregulation of SCD1/FADS2 could enhance the oncogenic capacities of ovarian cancer cells when cocultured in ascites or omental conditioned medium (OCM). In contrast, pharmaceutical or genetic inhibition of SCD1/FADS2 led to reduced cell proliferation, cell migration and invasion, and tumor growth through induction of G1/S cell-cycle arrest, ER stress, and cell death. Further investigation using transcriptome analysis revealed that depletion of SCD1 and FADS2 was associated with ferroptotic activities. By genetic or pharmaceutical inhibition of SCD1/FADS2, both the Glutathione/Glutathione disulfide (GSH/GSSG) ratio and Glutathione Peroxidase 4 (GPX4) level were reduced. This caused the abruption of the cellular redox balance, leading to elevation of intracellular reactive oxygen species (ROS), and iron-mediated lipid peroxidation in ascites-derived ovarian cancer cells. Moreover, inhibition of SCD1/FADS2 significantly reversed the expression changes of cell differentiation and EMT-related activities, accompanied by CSCs capacity suppression in ovarian cancer cells. Hence, depletion of SCD1/FADS2 could impair cancer stem cell (CSC) formation, platinum-resistance, and other oncogenic properties of EOC cells. Noticeably, the combination of SCD1/FADS2 inhibitors and cisplatin in drug treatment could synergistically inhibit in vivo tumor growth and tumor cell dissemination without causing any toxicity. Taken together, the aberrant upregulation of lipid desaturases SCD1/FADS2 in the ascites-derived ovarian cancer cells plays a crucial role in the lipid metabolic-derived oncogenic properties and redox-driven ferroptosis of ovarian cancer cells. Targeting SCD1/FADS2 by using specific inhibitors could significantly impair CSC formation, platinum-resistance, and tumor aggressiveness of ovarian cancer cells. Importantly, a synergistic drug combination of SCD1/FADS2 inhibitors and cisplatin provides a promising chemotherapeutic strategy for efficiently eradicating platinum-resistance and metastatic recurrence in peritoneal metastasis of EOC.