Sphingolipids influence tumor microenvironment in different malignancies. Estrogen and estrogen metabolites are involved in prostate cancer. Fingolimod is Sphingokinase-1 (SphK1) inhibitor which possesses anticancer properties in various tumor types. The aim of the current study is to investigate the interference of Fingolimod with the cross talk between sphingolipid and estrogen metabolisms within prostate cancer cells as a novel therapeutic strategy. The design is based on determining the mutual influence between estrogen metabolism/signaling and sphingolipid metabolism within prostate cancer cells. Cytotoxicity using SRB-U assay; cell cycle analysis using DNA cytometry and intracellular caspase-3 concentration were assessed. Estrogen metabolites and estrogen metabolizing enzymes were determined using LC/MS and RT-PCR, respectively. Estrogen receptor (ERα and ERβ) expression and their downstream signaling (CXCR4 and Cyclin-D1, respectively) were measured using immunocytochemical staining and RT-PCR, respectively. Fingolimod showed antiproliferative/cytotoxic effects against different prostate cancer cells (LNCaP, DU145 and PC3) with IC50 ranging from 3.0±0.3 to 6.8±1.7 µM. Fingolimod induced significant decrease in estradiol, estrone, 4-hydroxyestradiol and 16α-hydroxyestrone concentrations with reciprocal increase in 2-methoxyestrone and 2-methoxyestradiol concentrations. This was mirrored by significant down expression for the enzymes, aromatese, CYP1A1 and CYP1B1 and over expression for the enzyme COMT. Additionally, Fingolimod suppressed the expression of ERα and ERβ within prostate cancer cells as well as their downstream signaling (CXCR4 and Cyclin-D1, respectively). Reciprocally, it was found that estradiol and catechol estrogens induce the expression of SphK1 while methoxylated catechol estrogen suppresses its expression. Our results give compelling evidence that Fingolimod has therapeutic potential by modulating the estrogenic micromilieu and interrupting its cross talk with sphingolipid metabolism in prostate cancer cells.

Citation Format: Rasha M. Allam, Ahmed M. Al-Abd, Alaa Khedr, Ola A. Sharaf, Salwa M. Nofal, Amani E. Khalifa, Hisham A. Mosli, Ashraf B. Abdel-Naim. Therapeutic potential of fingolimod against prostate cancer cells is partly attributed to interrupting the cross talk between estrogen and sphingolipid metabolisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2115. doi:10.1158/1538-7445.AM2017-2115