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Coordinate involvement of cell cycle arrest and apoptosis strengthen the effect of FTY720
Y Nagahara1, Y Matsuoka, K Saito
1Division of Research Promotion, National Children's Medical Research Center, 3-35-31 Taishido, Setagaya-ku, Tokyo 154-8509, Japan.
Abstract:
A novel reagent, FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride), has been shown to induce a significant decrease of lymphocytes and lymphoma cells and is expected to be a potent immunosuppressant and anti-tumor drug. The decrease in lymphocytes and lymphoma cells is mainly the result of FTY720-induced apoptosis. FTY720 directly affects mitochondria and induces cell death. Moreover, FTY720 activates protein phosphatase (PP) 2A and affects anti-apoptotic intracellular signal transduction proteins to attenuate the anti-apoptotic effect. In this study, we examined the relationship between FTY720-induced apoptosis and cell cycle regulation. FTY720 induced apoptosis significantly at the G0 / G1 phase and caused G0 / G1 cell cycle arrest of the human lymphoma cell lines HL-60RG and Jurkat. Simultaneously, retinoblastoma protein (pRB) was dephosphorylated, suggesting that dephosphorylation of pRB was related to FTY720-induced G0 / G1 cell cycle arrest. Because this dephosphorylation was completely blocked by a specific PP1 / 2A inhibitor, okadaic acid, it appears that FTY720-activated PP2A is essential for FTY720-induced cell cycle arrest. FTY720-induced apoptosis was inhibited by Bcl-2 overexpression in Jurkat cells, but this did not prevent FTY720-induced cell cycle arrest, suggesting that the mechanism of FTY720-induced cell cycle arrest is independent of the mechanism of FTY720-induced apoptosis. These two independent pathways strengthen the effect of FTY720.
Insights
FTY720 induces lymphoma cell death through apoptosis and cell cycle arrest. These two independent pathways, involving mitochondrial effects and protein phosphatase 2A activation, enhance FTY720
Area of Science:
- Immunology and Cancer Biology
- Cellular and Molecular Pharmacology
Background:
- FTY720 (Fingolimod) is a novel reagent with immunosuppressive and anti-tumor potential.
- FTY720 induces lymphocyte and lymphoma cell death primarily through apoptosis.
- FTY720 impacts cellular processes including mitochondrial function and protein phosphatase (PP) 2A activation.
Purpose of the Study:
- To investigate the relationship between FTY720-induced apoptosis and cell cycle regulation.
- To elucidate the specific mechanisms underlying FTY720's effects on lymphoma cells.
Main Methods:
- Treatment of human lymphoma cell lines (HL-60RG and Jurkat) with FTY720.
- Analysis of cell cycle progression and apoptosis induction.
- Assessment of retinoblastoma protein (pRB) phosphorylation status.
- Use of specific inhibitors (okadaic acid) and genetic manipulation (Bcl-2 overexpression).
Main Results:
- FTY720 induced significant apoptosis and G0/G1 cell cycle arrest in lymphoma cells.
- Dephosphorylation of retinoblastoma protein (pRB) was observed, linked to G0/G1 arrest.
- FTY720-activated PP2A was essential for the observed cell cycle arrest.
- Bcl-2 overexpression inhibited FTY720-induced apoptosis but not cell cycle arrest.
Conclusions:
- FTY720 triggers apoptosis and cell cycle arrest through independent mechanisms.
- FTY720-activated PP2A plays a crucial role in FTY720-induced G0/G1 cell cycle arrest.
- The dual action of FTY720 on apoptosis and cell cycle regulation contributes to its potent anti-lymphoma effects.