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Vol. 53, Issue 4, 602-612, April 1998
Laboratory of Signal Transduction and Leukocyte Biology (C.G.,
A.S-B., F.M.), Instituto de Biología y Genética
Molecular, Facultad de Medicina, Consejo Superior de Investigaciones
Científicas-Universidad de Valladolid, E-47005 Valladolid,
Spain, and
Max-Planck-Institut für Immunbiologie (M.M.), D-79108
Freiburg, Germany
The ether phospholipid
1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine
(ET-18-OCH3; edelfosine) is a potent inducer of apoptosis
in human tumor cells. We show that ET-18-OCH3-induced apoptosis is associated with activation of the c-Jun
NH2-terminal kinase (JNK) signaling. The addition of
ET-18-OCH3 to distinct human leukemic cells (HL-60, U937,
and Jurkat), which undergo rapid apoptosis on treatment with
ET-18-OCH3, induced a dramatic and sustained increase in
the of c-jun mRNA level that was associated with
activation of activator protein-1 transcription factor. We found that
ET-18-OCH3 induced a persistent activation of JNK in HL-60
cells that was detected before the onset of apoptosis, the latter being
assessed by DNA fragmentation and by the appearance of
phosphatidylserine on the external leaflet of the plasma membrane. The
inductions of JNK after HL-60 monocyte/macrophage differentiation and
ET-18-OCH3-mediated apoptosis were distinguished by the
different activation patterns, transient versus persistent,
respectively. ET-18-OCH3 analogues unable to induce
apoptosis failed to activate JNK. ET-18-OCH3-dependent JNK
activation was not detected in K562 cells, which did not undergo
apoptosis on treatment with ET-18-OCH3. Phorbol myristate
acetate inhibited both ET-18-OCH3-induced apoptosis and
sustained JNK activation; thus, persistent JNK activation by
ET-18-OCH3 is associated with the capacity of this ether
phospholipid to induce apoptosis. Furthermore, antisense
oligonucleotides directed against c-jun blocked
ET-18-OCH3-induced apoptosis, indicating a role for c-Jun
in this apoptotic response. These data indicate that JNK activation and
c-Jun are involved in the induction of apoptosis by
ET-18-OCH3.
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