Synergistic effect of obeticholic acid and fasting-mimicking on proliferative, migration, and survival signaling in prostate cancer

Abstract

The systemic and resistant nature of the androgen-independent stage of prostate cancers makes it largely incurable even after intensive multimodal therapy. Apoptosis and epithelial-mesenchymal transition (EMT) are two fundamental events that are deeply linked to carcinogenesis. Hence, it is necessary to find a new combination of several therapies targeting apoptosis and EMT without causing side effects. Several recent studies have indicated that the Farnesoid X receptor is extensively associated with human tumorigenesis. The FXR agonist obeticholic acid (INT 747) has preliminarily exhibited a tumor suppressor potential. In this present study, we assess the potential synergism of FXR activation under nutrient deprivation in prostate cancer cell lines to investigate whether FXR activation enhances starvation-induced apoptosis in PC3 cells. In this study, PC-3 treatment with INT 747 significantly repressed cell proliferation and clonogenic potential. In addition, it significantly induced apoptosis of PC-3 cells and decreased their cancerogenic potential, as evaluated by annexin v apoptosis and transwell migration assay, respectively. The decreased expression of pro-caspase 3 by western blot analysis further confirmed INT 747-induced apoptosis. Furthermore, the fasting-mimicking diet (FMD) potentiated the antiproliferative, pro-apoptotic, and antimetastatic effects of INT 747. Mechanistically, these effects were mediated through the downregulation of cyclin D1 and upregulation of PTEN. In conclusion, INT 747 alone markedly decreases, and when combined with FMD abrogates the growth and migration of PC-3 cells.