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Theranostics 2022; 12(7):3534-3552. doi:10.7150/thno.70194 This issue Cite

Research Paper

SCD1/FADS2 fatty acid desaturases equipoise lipid metabolic activity and redox-driven ferroptosis in ascites-derived ovarian cancer cells

Yang Xuan¹, Huogang Wang¹, Mingo MH Yung¹, Fushun Chen¹, Wai-Sun Chan¹, Yau-Sang Chan¹, Stephen KW Tsui², Hextan YS Ngan¹, Karen KL Chan^1✉, David W Chan^1,2✉

1. Department of Obstetrics & Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China.
2. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China.

✉ Corresponding authors: Dr. David W CHAN, Department of Obstetrics and Gynaecology, L747 Laboratory Block, LKS Faculty of Medicine, 21 Sassoon Road, Pokfulam, Hong Kong SAR, P.R. China; E-mail: dwchanhk, and 5/F Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, CUHK. Phone: (852) 3943-6053; Fax: (852) 2603-5123; E-mail: dwchanedu.hk,; or Dr. Karen KL CHAN, Department of Obstetrics & Gynaecology, 6/F Professorial Block, Queen Mary Hospital, Pokfulam, Hong Kong SAR, P.R. China; E-mail: kklchanhk. More

Abstract

Rationale: Malignant ascites in peritoneal metastases is a lipid-enriched microenvironment and is frequently involved in the poor prognosis of epithelial ovarian cancer (EOC). However, the detailed mechanisms underlying ovarian cancer (OvCa) cells dictating their lipid metabolic activities in promoting tumor progression remain elusive.

Methods: The omental conditioned medium (OCM) was established to imitate the omental or ascites microenvironment. Mass spectrometry, RT-qPCR, IHC, and western blot assays were applied to evaluate human fatty acid desaturases expressions and activities. Pharmaceutical inhibition and genetic ablation of SCD1/FADS2 were performed to observe the oncogenic capacities. RNA sequencing, lipid peroxidation, cellular iron, ROS, and Mito-Stress assays were applied to examine ferroptosis. OvCa patient-derived organoid and mouse model of peritoneal metastases were used to evaluate the combined effect of SCD1/FADS2 inhibitors with cisplatin.

Results: We found that two critical fatty acid desaturases, stearoyl-CoA desaturase-1 (SCD1) and acyl-CoA 6-desaturase (FADS2), were aberrantly upregulated, accelerating lipid metabolic activities and tumor aggressiveness of ascites-derived OvCa cells. Lipidomic analysis revealed that the elevation of unsaturated fatty acids (UFAs) was positively associated with SCD1/FADS2 levels and the oncogenic capacities of OvCa cells. In contrast, pharmaceutical inhibition and genetic ablation of SCD1/FADS2 retarded tumor growth, cancer stem cell (CSC) formation and reduced platinum resistance. Inhibition of SCD1/FADS2 directly downregulated GPX4 and the GSH/GSSG ratio, causing disruption of the cellular/mitochondrial redox balance and subsequently, iron-mediated lipid peroxidation and mitochondrial dysfunction in ascites-derived OvCa cells.

Conclusions: Combinational treatment with SCD1/FADS2 inhibitors and cisplatin synergistically repressed tumor cell dissemination, providing a promising chemotherapeutic strategy against EOC peritoneal metastases.

Keywords: ovarian cancer, peritoneal metastases, lipid metabolism, lipid desaturases, oxidative stress

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