الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Prostate cancer is the second most frequently occurring cancer in males, with approximately 1.1 million new diagnoses per year and is predicted to be the leading cause of cancer-related death in men over the next decade. Several studies demonstrated that estrogens, estrogen metabolites, estrogen receptors and estrogen receptor downstream signaling were involved in prostate cancer development and progression. Sphingolipids and sphingosine kinase 1 have emerged as new players in the tumor microenvironment and cancer progression during the last decade. Indeed, sphingolipids were added to the list of estrogen activated mediators, regulating diverse cellular processes important for estrogen related cancer progression. FTY720, the first clinically approved sphingosine kinase 1 inhibitor, has emerged as a key player in cancer therapy as it has shown antitumor efficacy both in vivo and in vitro in multiple types of cancer including prostate cancer.
In this study, based on the established link between sphingolipid pathways and steroid hormones, we aimed to investigate the in-vitro chemotherapeutic effect of FTYY720 against prostate cancer cells with emphasis on estrogenic microenvironment. We found that FTY720 treatment resulted in significant decrease in the concentration of estrogens [estradiol and estrone] and hydroxylated estrogens (4-hydroxyestradiol and16α-hydroxyestrone), compared to control cells. These hydroxylated estrogens are known to show potent genotoxic and mitogenic properties. Accordingly, the expression of estrogen synthesizing enzymes (aromatase, CYP1A1 and CYP1B1) was significantly decreased within prostate cancer cells after treatment with FTY720 compared to untreated counterpart. On the other hand, treatment with FTY720 significantly increased the concentration of methoxy estrogens (2-methoxyestrone and 2-methoxyestradiol), compared to control cells. These methoxy estrogens were shown to have antiproliferative, proapoptotic, and antiangiogenic properties. Accordingly the expression level of estrogen inactivating enzyme (COMT) was significantly increased. Regarding estrogen receptors, FTY720 treatment diminished the estradiol stimulated expression of estrogen receptor α and basal expression of estrogen receptor β. Furthermore, FTY720 reduced the expression of the estrogen receptor-regulated genes CXCR4 and Cyclin D1. Finally, to show the other side of the relationship between sphingolipid pathways and steroid hormones in prostate cancer cells, we found that estradiol and 4-hydroxyestradiol cause significant increase in sphingosine kinase 1 expression, however, 2-methoxyestradiol cause significant decrease in its expression. In conclusion, the present study suggested a novel therapeutic potential of FTY720 in treating advanced and metastatic prostate cancer by influencing multiple targets of estrogen environment in prostate cancer.