Abstract 5811: Ovarian cancer cell fate is regulated by the balance between saturated and unsaturated fatty acids

Abstract

Abstract Background: Fat represents an important source of energy for ovarian cancer (OC) cells and is supplied either through import from the tumor milieu or via de novo lipogenesis. During fast tumor growth, when nutrients are scarce, lipogenesis becomes the primary source of fatty acids. Stearoyl-CoA desaturase (SCD), a rate-limiting enzyme in this pathway converts saturated (SFAs) into unsaturated fatty acids (UFAs) and is highly expressed in OC. The goal of this study was to determine how the balance between SFAs and UFAs tightly controlled by SCD, regulates OC cell survival and tumorigenicity. Methods: SCD was knocked down by shRNA or inhibited by using the small molecule CAY10566 and global effects on the lipidome and transcriptome were examined by targeted and untargeted lipidomics, stimulated Raman spectroscopy (SRS), and RNA sequencing. In OC cells in which SCD was blocked or knocked down, the effects of exogenous SFAs and UFAs on cell survival and endoplasmic reticulum (ER) stress pathway were assessed by using annexin V staining, XBP1 splicing assay and Western blotting of PERK/eIF2α/ATF4. Tumorigenicity was assessed by using an intraperitoneal (i.p.) xenograft model in nude mice. Results: RNA-seq analysis of SCD knockdown cells cultured under low serum conditions revealed activation of ER stress response pathways. Targeted lipidomics and SRS microscopy showed downregulation of UFAs vs. SFAs, while untargeted lipidomics discovered decreased fatty acyl chain plasticity among phosphatidylcholines. Activation of IRE1α/XBP1 and PERK/eIF2α/ATF4 axes was observed in cells accumulating SFAs. Stiff and disorganized ER membrane was detected by electron microscopy and Raman spectroscopy. Annexin V staining demonstrated apoptosis of OC cells under long-term mild ER stress or short-time severe ER stress induced by increased levels of SFAs. ER stress and apoptosis were rescued by addition of UFAs. In vivo SCD knockdown suppressed tumor growth and treatment with the SCD inhibitor CAY10566 reduced the number of metastases and the volume of ascites in mice fed with SFA enriched diet, but not in mice fed a balanced diet. Conclusion: Our data support that OC cells are highly susceptible to unbalanced intracellular SFAs/UFAs, undergoing ER stress and apoptosis in the presence of excessive intracellular SFAs. SCD inhibition coupled with a diet rich in saturated fats decreased cancer progression in vivo. These results support SCD as a key regulator of cancer cell fate during metabolic stress in growing tumors and point to new treatment strategies targeting lipid metabolism. Citation Format: Guangyuan Zhao, Yuying Tan, Horacio Cardenas, David Vayngart, Yinu Wang, Christina Ferreira, Ji-Xin Cheng, Daniela Matei. Ovarian cancer cell fate is regulated by the balance between saturated and unsaturated fatty acids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5811.