Department of Pharmacology, National Research Centre, Giza, Egypt.
Department of Pharmacology, National Research Centre, Giza, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
Toxicol Lett. 2018 Jul;291:77-85. doi: 10.1016/j.toxlet.2018.04.008. Epub 2018 Apr 11.
Sphingolipids are critical regulators of tumor microenvironments and play an important role in estrogen-dependent cancers. Estrogen and estrogen metabolites were found to be involved in prostate cancer. Fingolimod (FTY720) is a sphingokinase-1 (SphK1) inhibitor with anticancer properties against various tumor cell types. Herein, we investigated the interference of FTY720 with the cross talk between sphingolipid metabolism and estrogen metabolism within prostate cancer cells. FTY720 showed cytotoxic antiproliferative effects against androgen-dependent and -independent prostate cancer cells with IC ranging from 3.0 ± 0.3 to 6.8 ± 1.7 μM. Exposure of prostate cancer cells to FTY720 resulted in a dramatic decrease in the concentration of estradiol, estrone, 4-hydroxyestradiol and 16α-hydroxyestrone compared to control cells. However, FTY720 significantly increased the concentration of 2-methoxyestrone and 2-methoxyestradiol within prostate cancer cells. This was mirrored by significant downregulating of the expression of estrogen and catechol estrogen-synthesizing enzymes (CYP19, CYP1A1 and CYP1B1) within prostate cancer cells. On the other hand, FTY720 significantly upregulated the expression of catechol estrogen-detoxifying enzyme (COMT). Additionally, FTY720 abolished estrogen-stimulated expression of ERα and basal expression of ERβ within prostate cancer cells. Furthermore, FTY720 suppressed the expression of the ER-downstream regulated genes, CXCR4 and cyclin D1. Reciprocally, it was found that estradiol and catechol estrogens significantly induced the expression of SphK1 while methoxylated catechol estrogen suppressed its expression within prostate cancer cells in a dose-dependent manner. Current research has highlighted the hazardous influence of the estrogenic component to prostate cancer. We found that fingolimod (FTY720) could modulate the estrogenic micromilieu and interrupt its cross talk with sphingolipid metabolism.
鞘脂是肿瘤微环境的关键调节因子，在雌激素依赖性癌症中发挥重要作用。雌激素和雌激素代谢物被发现参与前列腺癌。芬戈莫德（FTY720）是一种鞘氨醇激酶-1（SphK1）抑制剂，对各种肿瘤细胞类型具有抗癌特性。在此，我们研究了 FTY720 对前列腺癌细胞中鞘脂代谢与雌激素代谢之间串扰的干扰。FTY720 对雄激素依赖性和非依赖性前列腺癌细胞表现出细胞毒性抗增殖作用，IC 范围为 3.0±0.3 至 6.8±1.7μM。与对照细胞相比，暴露于 FTY720 的前列腺癌细胞中雌二醇、雌酮、4-羟基雌二醇和 16α-羟基雌酮的浓度明显降低。然而，FTY720 显著增加了前列腺癌细胞内 2-甲氧基雌酮和 2-甲氧基雌二醇的浓度。这与前列腺癌细胞中雌激素和儿茶酚雌激素合成酶（CYP19、CYP1A1 和 CYP1B1）的表达显著下调相吻合。另一方面，FTY720 显著上调儿茶酚雌激素解毒酶（COMT）的表达。此外，FTY720 消除了雌激素刺激的前列腺癌细胞中 ERα 的表达和 ERβ 的基础表达。此外，FTY720 抑制了 ER 下游调节基因 CXCR4 和细胞周期蛋白 D1 的表达。相反，发现雌二醇和儿茶酚雌激素显著诱导 SphK1 的表达，而甲氧基儿茶酚雌激素以剂量依赖的方式抑制前列腺癌细胞中 SphK1 的表达。目前的研究强调了雌激素成分对前列腺癌的有害影响。我们发现，芬戈莫德（FTY720）可以调节雌激素微环境并中断其与鞘脂代谢的串扰。
