Abstract:
Emerging evidence links periprostatic adipose tissue (PPAT) inflammation, a consequence of metabolic impairment, to certain features of prostate cancer (PCa) aggressiveness. AT thromboinflammation, mediated by the proteolytic activation of protease-activated receptors (PARs) particularly thrombin and Factor Xa (FXa), drives AT dysfunction. Nevertheless, the contribution of PPAT thromboinflammation to the early prostatic neoplastic alterations associated with mild metabolic impairment have not been investigated. Here, we utilized a non-obese prediabetic rat model to assess prostatic neoplasia in association with PPAT thromboinflammation. Mild hypercaloric diet (MHC)-fed rats exhibited hyperinsulinemia, insulin resistance, hypertriglyceridemia, a lower metabolic efficiency, and a higher fat/lean ratio in comparison to regular chow-fed rats. When compared to regular chow-fed rats, MHC-fed rats exhibited PPAT with hypertrophied adipocytes, enhanced oxidative stress, and increased proinflammatory macrophage infiltration. Particularly, PPAT of MHC-fed rats exhibited enhanced fibrin deposition indicative of increased PPAT FXa activity. Concurrently, prostates from MHC-fed rats displayed a higher number of prostatic intraepithelial neoplasia (PIN), pronounced fibrosis, increased proinflammatory macrophage influx, and enhanced expression of hyperproliferative and epithelial-to-mesenchymal (EMT) markers. Importantly, these prostatic and adipocytic manifestations were attenuated in MHC-fed rats treated with a non-hemorrhagic dose of rivaroxaban, a direct FXa inhibitor. Furthermore, we investigated the possible direct effects of rivaroxaban on murine Plum- AD androgen-dependent Pten-/- p53-/- prostatic epithelial cancer cells in vitro. Rivaroxaban inhibited Plum-AD proliferation, migration, and colony formation, in addition to enhancing oxidative stress. While the anti-proliferative effect can be explained by rivaroxaban-mediated inhibition of PAR-2 signaling, rivaroxaban-mediated inhibition of Plum-AD migration, and colony formation seems to be independent of PAR-2 signaling. As such, further investigation is required to delineate the molecular underpinnings of rivaroxaban-associated amelioration of PPAT thromboinflammation and the associated prostatic neoplastic alterations secondary to metabolic dysfunction.