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Fingolimod interrupts the cross talk between estrogen metabolism and sphingolipid metabolism within prostate cancer
Rasha M Allam1, Ahmed M Al-Abd2, Alaa Khedr3
1Department of Pharmacology, National Research Centre, Giza, Egypt.
Abstract:
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 IC50 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.
Insights
Fingolimod (FTY720) inhibits prostate cancer growth by altering estrogen metabolism and sphingolipid pathways. This drug reduces harmful estrogen metabolites while increasing protective ones, disrupting cancer cell proliferation.
Area of Science:
- Oncology
- Biochemistry
- Endocrinology
Background:
- Sphingolipids regulate tumor microenvironments and are crucial in estrogen-dependent cancers like prostate cancer.
- Estrogen and its metabolites are implicated in prostate cancer development and progression.
- Fingolimod (FTY720), a sphingokinase-1 inhibitor, exhibits anticancer properties.
Purpose of the Study:
- To investigate how FTY720 affects the interplay between sphingolipid and estrogen metabolism in prostate cancer cells.
- To determine the impact of FTY720 on estrogen metabolite levels and related enzyme expression.
- To explore FTY720's influence on estrogen receptor signaling and downstream targets.
Main Methods:
- Assessing FTY720's cytotoxic and antiproliferative effects on prostate cancer cells.
- Quantifying estrogen metabolite concentrations after FTY720 exposure.
- Measuring the expression levels of key enzymes involved in estrogen synthesis, metabolism, and detoxification (CYP19, CYP1A1, CYP1B1, COMT).
- Analyzing the expression of estrogen receptors (ERα, ERβ) and downstream genes (CXCR4, cyclin D1).
Main Results:
- FTY720 demonstrated significant cytotoxic and antiproliferative effects (IC50: 3.0–6.8 μM) against prostate cancer cells.
- FTY720 decreased levels of estradiol, estrone, 4-hydroxyestradiol, and 16α-hydroxyestrone while increasing 2-methoxyestrone and 2-methoxyestradiol.
- FTY720 downregulated estrogen-synthesizing enzymes (CYP19, CYP1A1, CYP1B1) and upregulated catechol estrogen-detoxifying enzyme (COMT).
- FTY720 abolished estrogen-stimulated ERα and basal ERβ expression, suppressed CXCR4 and cyclin D1 expression.
- Estradiol and catechol estrogens induced SphK1 expression, while methoxylated metabolites suppressed it.
Conclusions:
- FTY720 effectively modulates the estrogenic microenvironment within prostate cancer cells.
- The drug interrupts the cross-talk between sphingolipid metabolism and estrogen metabolism, offering a potential therapeutic strategy.
- FTY720's ability to alter estrogen metabolite profiles and receptor signaling highlights its potential in combating prostate cancer.
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