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Caspase Activation Is Required for Nitric Oxide-Mediated,
CD95(APO-1/Fas)-Dependent and Independent Apoptosis in Human
Neoplastic Lymphoid Cells
Katerina Chlichlia,
Marcus E. Peter,
Marian Rocha,
Carsten Scaffidi,
Mariana Bucur,
Peter H. Krammer,
Volker Schirrmacher, and
Victor Umansky
From the Division of Cellular Immunology and the Division of
Immunogenetics, Tumor Immunology Program, German Cancer Research
Center, Heidelberg, Germany.
Nitric oxide (NO), an important effector molecule
involved in immune regulation and host defense, was shown to induce
apoptosis in lymphoma cells. In the present report the NO donor
glycerol trinitrate was found to induce apoptosis in Jurkat cells that are sensitive to CD95-mediated kill. In contrast, a CD95-resistant Jurkat subclone showed substantial protection from apoptosis after exposure to NO. NO induced mRNA expression of CD95 (APO-1/Fas) and
TRAIL/APO-2 ligands. Moreover, NO triggered apoptosis in freshly isolated human leukemic lymphocytes which were also sensitive to
anti-CD95 treatment. The ability of NO to induce apoptosis was
completely blocked by a broad-spectrum ICE (interleukin-1 converting
enzyme)-protease/caspase inhibitor and correlated with FLICE/caspase-8 activation. This activation was abrogated in some neoplastic lymphoid cells but not in others by the inhibitor of protein
synthesis cycloheximide. Our results were confirmed using an in vitro
experimental model of coculture of human lymphoid target cells with
activated bovine endothelial cells generating NO as effectors.
Furthermore, the inhibition of endogenous NO production with the
inducible NO synthase inhibitor NG-monomethyl-L-arginine
caused a complete abrogation of the apoptotic effect. Our data provide
evidence that NO-induced apoptosis in human neoplastic lymphoid cells
strictly requires activation of caspases, in particular FLICE, the most
CD95 receptor-proximal caspase. Depending on the cell line tested this
activation required or was independent of the CD95 receptor/ligand
system.
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4311-4320
© 1998 by The American Society of Hematology.
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