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Receptor Activator of Nuclear Factor B Ligand Plays a Nonredundant Role in Doxorubicin-induced Apoptosis¹

University Children’s Hospital Tübingen, Department of General Pediatrics, Hematology and Oncology, 72076 Tuebingen, Germany [I. M., S. M. P., U. G., D. N., G. B.], and St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 [J. Z., R. H.]

Doxorubicin induces apoptosis in a variety of cells. We investigated the expression and function of various tumor necrosis factor (TNF)-homologues and their receptors. CEM cells did not differentially express any one of the TNF-homologous receptors investigated nor TNF-related apoptosis-inducing ligand or TNF-related weakly apoptosis-inducing ligand (TWEAK) in the presence of doxorubicin. In addition to CD95 ligand, however, receptor activator of nuclear factor B ligand (RANKL) was strongly up-regulated. Doxorubicin-induced apoptosis was greatly suppressed in the presence of either neutralizing antibody or RANK-Fc fusion protein. Moreover, neutralizing RANKL also prevented cytochrome c release from mitochondria. RANKL alone was unable to induce significant levels of apoptosis in CEM cells. However, doxorubicin-induced apoptosis was increased >2-fold when exogenous RANKL was added. Therefore, RANKL is necessary but not sufficient to account for early doxorubicin-induced apoptosis in CEM cells. This finding suggests improved chemotherapeutic efficiency of the anthracyclin against susceptible malignant cells in the presence with RANKL.

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