Abstract
Abstract
Sphingokinase-1/sphingosine-1-phosphate pathway contributes significantly to progression of different types of cancer which has been recently reported to influence estrogen level in breast cancer cells. Current evidence suggests that estrogen (E2) and its metabolites, especially catechol metabolites, are playing a key role in the proliferation and carcinogenesis of the prostate glands. FTY720 is Sphingokinase-1inhibitorwhich possess anticancer properties in various tumor cell types. The aim of this study is to investigate the chemotherapeutic effect of FTYY720 against prostate cancer cells with emphasis on estrogenic microenvironment in-situ. The IC50 of FTY720 in DU145 cell line was4.2±1.4µg/ml. The concentration of estrogen and its metabolites were assayed in the media over DU145 cells using liquid chromatography tandem mass (LC/MS) technique. FTY720 treatment resulted in a dramatic decrease in estradiol (E2) and estrone (E1) levels compared to control untreated cells (2652.76±115.62 vs. 725.69±1.28 and 283.36±4.18vs. 150.32±8.96ng/g, respectively); however, it had no significant effect on the concentration of Estriol(E3). In terms of catechol estrogens, 4-hydroxyEstradiol (4-OHE2) and 2-hydroxy Estradiol (2-OHE2) formation was significantly decreased after treatment withFTY720 compared to control cells (25.42±2.40 vs. 7.45±0.82 and 485.93±3.10 vs. 477.42±4.24 ng/g), respectively. FTY720 had no significant effect on formation of 16α-hydroxyEstrone (16 α-OHE1). On the other hand, treatment with FTY720 significantly increased the concentration of 2-methoxyestrone (2-MOHE1) and 2-methoxyestradiol (2-MOHE2) compared to control cells (5.45±0.12 vs. 29.94±2.97 and165.62±5.67 vs. 269.97±15.85), respectively..The expression of catechol estrogen synthesizing enzymes (CYP19, CYP1A1 and CYP1B1) was significantly decreased within prostate cancer cells after treatment with FTY720 compared to untreated counterpart. On the other hand, the expression level of catechol estrogen degrading enzyme (COMT) was significantly decreased. Cell cycle analysis of DU145 cells showed arrest at G1 phase with significant decrease in the G2-M population due to treatment with FTY720. In conclusion, FTY720 induced anti proliferative effect in prostate cancer cells might be attributed partly to its influence on estrogen metabolism in-situ.
Citation Format: Rasha M. Allam, Hisham A. Mosli, Amany E. Khalifa, Salwa M. Nofal, Ola A. Sharaf, Ashraf B. Abdel-Naim, Ahmed M. Al-Abd. Antiproliferative effect of fingolimod (FTY720) in human prostate cancer cells: Insights to estrogen metabolism in situ. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3800. doi:10.1158/1538-7445.AM2014-3800