Coordinate involvement of cell cycle arrest and apoptosis strengthen the effect of FTY720.
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.
Nagahara
Y
Y
Division of Research Promotion, National Children's Medical Research Center, 3-35-31 Taishido, Setagaya-ku, Tokyo 154-8509, Japan.
Matsuoka
Y
Y
Saito
K
K
Ikekita
M
M
Higuchi
S
S
Shinomiya
T
T
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation; D004789:Enzyme Activation; D000068876:Fingolimod Hydrochloride; D018922:HL-60 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011409:Propylene Glycols / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives; D013997:Time Factors
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016160:Retinoblastoma Protein; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases; D001973:Bromodeoxyuridine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine