Receptor activator of nuclear factor kappaB ligand plays a nonredundant role in doxorubicin-induced apoptosis.
Doxorubicin induces apoptosis in a variety of cells. We investigated the expression and function of various tumor necrosis factor (TNF)alpha-homologues and their receptors. CEM cells did not differentially express any one of the TNFalpha-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 kappaB 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.
Müller
Ingo
I
University Children's Hospital Tübingen, Department of General Pediatrics, Hematology and Oncology, 72076 Tuebingen, Germany. ingo.mueller@med.uni-tuebingen.de
Pfister
Stefan M
SM
Grohs
Ulrike
U
Zweigner
Janine
J
Handgretinger
Rupert
R
Niethammer
Dietrich
D
Bruchelt
Gernot
G
D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D002460:Cell Line; D003574:Cytochrome c Group / Q000378:metabolism; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D019311:Staurosporine / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology
D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D003574:Cytochrome c Group; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D019311:Staurosporine