Oleic Acid Exhibits Anti-Proliferative and Anti-Invasive Activities via the PTEN/AKT/mTOR Pathway in Endometrial Cancer

SIMPLE SUMMARY: Metabolic reprogramming, especially fatty acid metabolism, is very strongly associated with carcinogenesis and progression of endometrial cancer. Increasing evidence revealed that oleic acid exhibited pro- and anti-tumor effects in different types of tumors, yet the mechanism underlying this dual effect on tumor growth remains unknown. In this study, we found that oleic acid significantly inhibited cell proliferation and tumor growth in endometrial cancer cells and a transgenic mouse model of endometrial cancer. Oleic acid increased lipogenesis and lipid droplets, and inhibition of the formation of lipid droplets resulted in an enhanced effect of oleic acid on inhibiting endometrial cancer cells. Importantly, oleic acid enhanced the expression of wild-type PTEN, while knockdown of PTEN or targeting AKT by ipatasertib partially reversed or amplified the effect oleic acid on cell proliferation and formation of lipid droplets, respectively. Thus, our results confirm that oleic acid inhibits cell growth depending on PTEN/AKT/mTOR pathway in endometrial cancer. ABSTRACT: Reprogramming of fatty acid metabolism promotes cell growth and metastasis through a variety of processes that stimulate signaling molecules, energy storage, and membrane biosynthesis in endometrial cancer. Oleic acid is one of the most important monounsaturated fatty acids in the human body, which appears to have both pro- and anti-tumorigenic activities in various pre-clinical models. In this study, we evaluated the potential anti-tumor effects of oleic acid in endometrial cancer cells and the LKB1(fl/fl)p53(fl/fl) mouse model of endometrial cancer. Oleic acid increased lipogenesis, inhibited cell proliferation, caused cell cycle G1 arrest, induced cellular stress and apoptosis, and suppressed invasion in endometrial cancer cells. Targeting of diacylglycerol acyltransferases 1 and 2 effectively increased the cytotoxicity of oleic acid. Moreover, oleic acid significantly increased the expression of wild-type PTEN, and knockdown of PTEN by shRNA partially reversed the anti-proliferative and anti-invasive effects of oleic acid. Inhibition of the AKT/mTOR pathway by ipatasertib effectively increased the anti-tumor activity of oleic acid in endometrial cancer cells. Oleic acid treatment (10 mg/kg, daily, oral) for four weeks significantly inhibited tumor growth by 52.1% in the LKB1(fl/fl)p53(fl/fl) mice. Our findings demonstrated that oleic acid exhibited anti-tumorigenic activities, dependent on the PTEN/AKT/mTOR signaling pathway, in endometrial cancer.