Abstract 3946: HDL associated Paraoxonase 1 reduces the ovarian tumorigenesis by enhancing the HDL function

Abstract

Abstract Background: Membrane lipids/cholesterol determines the fluidity, clustering of receptors and other protein interactions that delineate signaling pathways for cell cycle/proliferation. Emerging evidences suggest that highly proliferative cancer cells show a high lipid and cholesterol avidity and are considered as hallmarks of cancer aggressiveness including ovarian cancer. Paraoxonase 1 (PON1) is a high density lipoprotein (HDL) associated enzyme with a plethora of functions. PON1 deficiency aggravates HDL inflammatory index, systemic inflammation, and results in lipid retention associated diseases including atherosclerosis and hepatic steatosis. Meta-analysis studies documented that PON1 polymorphisms are associated with various cancers including ovarian cancer and PON1 activity is negatively correlated with human ovarian tumor size, providing clinical association between PON1 and ovarian cancers. Yet, the role and mechanism of action of PON1 in ovarian cancer development has not been elucidated. Hypothesis: We hypothesized that PON1 may inhibit the ovarian tumorigenesis by modulating HDL function. Methods and Results: In this report, in patients with ovarian cancer, we observed that plasma PON1 levels are higher, but with lower activity compared to healthy control. Immunoprecipitation of plasma PON1, followed by ELISA against oxidized lipids suggest that PON1 is oxidatively modified, specifically by 4-HNE. In addition, PON1 activity is negatively correlated with HDL pro-inflammatory index. Using a xenograft mouse model, we demonstrate that overexpression of PON1 prevents the development of ovarian cancer. HDL from xenograft transgenic mice shows less pro-inflammatory properties with increased cholesterol efflux efficiency from ovarian cancer cells. Mechanistically, PON1 impairs VEGF signaling in ovarian cancer cells by increasing cholesterol (Mitogenic factor) efflux, resulting in reduced dimerization of vascular endothelial growth factor receptor 2 (VEGF-2R) and VEGF-2R phosphorylation (angiogenic inducer) as well as downstream signaling pathways, including Akt and ERK1/2 which in turn reduce the cell proliferation and angiogenesis. Furthermore, cholesterol and VEGF levels are significantly lowered in the tumor microenvironment in PON1 transgenic mice but there are no changes in the gene expressions that are associated with either cholesterol synthesis or its degradation pathways. Conclusion: Taken together, we report for the first time that PON1 acts as a tumor suppressor of ovarian cancer by possibly reducing VEFG signaling and enhancing the HDL function, suggesting that activation of HDL associated PON1 might be a fruitful strategy to inhibit the ovarian tumor formation. Citation Format: Asokan Devarajan, Victor Grijalva, Dawoud Sulaiman, Feng Su, Ellen O'Connor, Robin Farias-Eisner, Srinivasa Reddy. HDL associated Paraoxonase 1 reduces the ovarian tumorigenesis by enhancing the HDL function [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3946.