Vol. 300, Issue 3, 939-945, March 2002

Distinct Pathways of Apoptosis Triggered by FTY720, Etoposide, and Anti-Fas Antibody in Human T-Lymphoma Cell Line (Jurkat Cells)

Masayuki Fujino¹ , Xiao-Kang Li¹ , Yusuke Kitazawa, Lei Guo, Mikiko Kawasaki , Naoko Funeshima, Takashi Amano and Seiichi Suzuki

Department of Experimental Surgery and Bioengineering, National Children's Medical Research Center, Tokyo, Japan (M.F., X.-K.L., Y.K., L.G., M.K., N.F., S.S.); and Department of Zootechnical Science, Tokyo University of Agriculture, Tokyo, Japan (M.K., T.A.)

2-Amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diol hydrochloride (FTY720), a synthetic product derived from a metabolite of Isaria sinclairii, has been demonstrated to have a potent immunosuppressive activity that induces apoptotic cell death in T cells and several other cell lines. In this study, using the human T-lymphoma cell line, Jurkat cells, we investigated the apoptotic signal transduction mediated by FTY720, in particular comparing its role on the cleavage of caspases, with that mediated by etoposide or anti-Fas antibody. All of these agents cleaved caspases, inducing their active form in the affected cells. Pretreatment with a broad caspase inhibitor [benzyloxycarbonyl-Val-Ala-Asp-(Ome) fluoromethyl ketone] markedly decreased the incidence of apoptotic cells induced by FTY720, etoposide, and anti-Fas antibody, through the abrogation of cleavage of Bid, poly(ADP-ribose) polymerase, and caspases 3, 8, and 9. The overexpression of Bcl-2 gene prevented FTY720- and etoposide-mediated apoptosis, but not Fas-mediated apoptosis. In addition, mitochondria were demonstrated to play a critical role in FTY720-triggered cell death, suggesting that this drug has a potent anticancer activity.