Oleic acid, a monounsaturated fatty acid, exhibits antiproliferative and anti-tumorigenic effects in pre-clinical studies for endometrioid endometrial cancer (261)

Abstract

<b>Objectives:</b> Oleic acid (OA), a monounsaturated fatty acid commonly found in olive oil, has been studied for its potential protective qualities in inflammatory conditions and cancers. In breast cancer cells, OA has been shown to reduce the expression of the oncogene <i>Her-2/ neu</i> and promote apoptosis. The relationship between the intake of olive oil and endometrial cancer risk and progression has been largely unexplored. Thus, we aimed to evaluate the effect of OA on cell proliferation and tumor growth in endometrial cancer cell lines and a transgenic mouse model of endometrial cancer. <b>Methods:</b> The human endometrioid endometrial cancer cell lines, ECC-1 and KLE, were exposed to varying concentrations of OA. Cell proliferation was assessed by MTT assay. Apoptosis was assessed by cleaved caspase-3, -8, and -9 assays. Cell cycle progression was measured by Cellometer. Cellular stress was measured by DCFH-DA assay. Mitochondrial membrane potential was assessed by TMRE assay. Western immunoblotting was performed to determine the effects of OA on BCL-xl, MCL-1, CDK4, CyclinD1, Calnexin, and Bip. The LKB1^fl/flp53^fl/fl mouse model of endometrioid endometrial cancer was used to determine the antitumorigenic activity of OA. The mice were treated with OA (10 mg/kg, oral gavage, daily) versus control for four weeks. <b>Results:</b> OA inhibited proliferation in a dose-dependent manner in both cell lines, with a 60% reduction at a dose of 500 µM in the ECC-1 cell line and 250 µM in the KLE cell line. OA at a dose of 200 µM significantly increased the activity of cleaved caspase-3, 8, and 9 by 2.2, 1.4, and 1.7-fold in the ECC-1 cells (p<0.05), respectively, and 1.4, 1.3, and 1.4-fold in the KLE cells (p<0.05), respectively. OA simultaneously decreased expression of Bcl-xl and MCL-1 in both cell lines. OA inhibited cell cycle progression by G1 phase arrest in both cell lines in a dose-dependent fashion (p=0.02) and decreased expression of the cell cycle-related proteins, CDK4, and cyclin D1. Treatment with OA significantly increased ROS production at doses of 50 and 200 µM (p<0.05) and induced Calnexin and Bip expression in both cell lines. TMRE assay showed decreased mitochondrial membrane potential with OA at doses of 50 and 200 µM (p<0.05). Treatment of LKB1^fl/flp53^fl/fl mice with OA was well-tolerated and reduced tumor weight by 53% compared with control mice (p<0.05). <b>Conclusions:</b> We found that OA, the main monounsaturated fatty acid of olive oil, had antiproliferative and antitumorigenic effects in endometrioid endometrial cancer. These findings provide a preclinical rationale for OA as a potential dietary intervention and therapeutic adjunct in endometrial cancer patients.