Palmitic acid, a common long-chain saturated fatty acid, demonstrates anti-proliferative and anti-tumorigenic effects in pre-clinical models of endometroid endometrial cancer (262)

Abstract

<b>Objectives:</b> The consumption of saturated free fatty acids, such as palmitic acid (PA), has been implicated in diseases related to lipotoxicity (i.e., obesity and diabetes), including cancer development. Although some studies have shown PA to have pro-tumorigenic effects, emerging evidence suggests that PA may also have antitumorigenic activity for some cancer types, including hepatocellular and breast cancer. The impact of PA on endometrial cancer (EC) development and progression has yet to be explored, despite EC being a highly obesity-driven disease. Thus, we aimed to delineate the effects of PA on cell proliferation and tumor growth in EC cell lines and a transgenic mouse model of EC. <b>Methods:</b> The human endometrioid EC cell lines ECC-1 and Ishikawa were used. Cell proliferation was assessed by MTT assay. Apoptosis was assessed by cleaved caspase-3 assay. Cellular stress was measured by DCFH-DA and JC1 assay. Adhesion was assessed by laminin-1 assay, whereas migration was determined by wound healing assay. Western immunoblotting was performed to determine the effects of PA on BCL-2, MCL-1, PERK, Bip, and PD1. The LKB1^fl/flp53^fl/fl mouse model of endometrioid EC was used in this study to determine the antitumorigenic activity of PA. Mice were treated with PA (10 mg/kg, oral gavage, daily) or control for four weeks. Immunohistochemistry of the endometrial tumors was performed to assess the effects of PA on cell proliferation as measured by Ki-67 staining. <b>Results:</b> PA potently inhibited cell proliferation in a dose-dependent manner in both cell lines with a median IC50 of 166µM and 356µM after 72 hours of treatment in ECC-1 and Ishikawa, respectively. PA (250µM) increased the activity of cleaved caspase-3 by 8.2-fold in ECC-1 and 2.9-fold in Ishikawa (p<0.05). Treatment with PA significantly increased ROS and JC1 production (p<0.05), and induced PERK, Bip, and PD1 expression in both cell lines. Cellular adhesion (decreased by 14% in ECC-1 and 14% in Ishikawa, p<0.05) and wound healing (decreased by 53% in ECC-1 and 55% in Ishikawa, p<0.05) were significantly impaired after treatment with PA in both cell lines. In LKB1^fl/flp53^fl/fl mice, PA decreased tumor weight by 44% (p<0.05) as compared to control mice, along with a corresponding decrease in the expression of Ki-67 in the endometrial tumor tissues (p<0.05). <b>Conclusions:</b> We found that PA, the most common saturated free fatty acid, had antiproliferative and antitumorigenic effects in endometrioid EC. Further studies are needed to assess if PA would be a novel dietary intervention in the treatment of EC.