Abstract 1472: Paraoxonase 3 is a novel tumor suppressor protein in xenograft mouse model

Introduction: Dysfunction of mitochondrial respiratory chains or its associated machinery favors the aerobic glycolysis leading to upregulation of genes related to cell proliferation, metastasis, drug resistant and cancer cell stemness, i.e., the Warburg effect, which has a major role in the pathogenesis of tumor formation. Various studies have documented that perturbation of mitochondria leads to apoptosis suggesting that the precise spatiotemporal regulation of mitochondrial function is a critical regulator of both cell survival and death, whcih determine tumorigenesis. Paraoxonase 3 (PON3) is an intracellular protein localized to the mitochondrial associated membrane. PON3 binds coenzymes Q10 and regulates the respiratory complex activity and prevents the ubisemiquinone-mediated mitochondrial superoxide levels in response to stress conditions. PON3 deficiency leads to dysfunction of mitochondria, which along with an increase in mitochondrial oxidative stress causes systemic inflammation, atherosclerosis, obesity and gall stone formation. PON3 is upregulated in ovarian cancer tissues. However, it9s expression in various stages of ovarian cancer and its role on cancer development have not been studied. Hypothesis: PON3 expression may regulate the ovarian cancer development by enhancing the mitochondrial function. Methods and Results: Using human ovarian carcinoma tissue array, we identified that PON3 expression was higher in both early and late stages of ovarian cancer when compared to normal tissue. Interestingly, we demonstrated that overexpression of PON3 prevented tumor formation in a mouse ovarian cancer xenograft model. Overexpression of PON3, (i) reduced the tumor angiogenesis marker, CD31 levels in the tumor microenvironment and (ii) inhibited ovarian cancer cell proliferation in both normoxic and hypoxic condition in vitro. Moreover, PON3 reduced VEGF levels (but not IGF-1 levels) under hypoxic conditions. Furthermore, mechanistically, overexpression of PON3 decreased the VEGF level by accelerating the proteasome-dependent protein degradation of hypoxia inducible factor-1 α (HIF-1α) under hypoxic conditions. Finally, we demonstrate that the inhibitory effect of PON3 on HIF-1α levels is, in part, mediated by mitochondrial function. Conclusion: We report for the first time that PON3 functions as a tumor suppressor in ovarian cancer possibly by suppressing VEGF signaling via HIF-1α by enhancing the mitochondrial function suggesting that PON3 might be a successful strategy to inhibit the ovarian cancer development. Citation Format: Asokan Devarajan, Feng Su, Dawoud Sulaiman, Dorothy Nguyen, Robin Farias-Eisner, Srinivasa T. Reddy. Paraoxonase 3 is a novel tumor suppressor protein in xenograft mouse model [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 1472.