Sensitization of melanoma cells to TRAIL by UVB-induced and NF-kappaB-mediated downregulation of xIAP.
Effective treatment of malignant melanoma with the tumor-selective death ligand tumor necrosis-related apoptosis-inducing ligand (TRAIL) is curtailed by the fact that many melanoma cell lines are a priori resistant against TRAIL-induced apoptosis. By investigating 18 melanoma cell lines, we show that TRAIL susceptibility is completely independent of the tumor progression stage but can be positively stimulated by co-exposure to a sublethal ultraviolet B light (UVB) dose, providing an excellent tool to study the mechanism underlying TRAIL resistance. TRAIL resistance could be linked to the ratio of x-linked inhibitor of apoptosis proteins (xIAP) and caspase-3 levels within the cell. UVB-induced sensitization coincides with enhanced xIAP degradation, allowing full caspase-3 processing and activation. It is also accompanied by concomitant IkappaBalpha degradation, resulting in nuclear factor-kappaB (NF-kappaB)-dependent transcriptional repression of xIAP. Loss of xIAP in turn was reduced upon overexpression of an IkappaBalpha super-repressor, thus NF-kappaB activation seems to be responsible for differential regulation of xIAP and consequently determines TRAIL susceptibility. As xIAP-mediated blockade of apoptosis seems to be the dominant cause of TRAIL resistance of all melanoma cell lines investigated here, our data suggest that direct chemical xIAP inhibition or combination treatment with DNA-damaging agents may offer new therapeutic strategies to generally sensitize melanoma toward TRAIL-induced apoptosis.
Thayaparasingham
B
B
Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
Kunz
A
A
Peters
N
N
Kulms
D
D
D017209:Apoptosis / Q000528:radiation effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D002478:Cells, Cultured; D015536:Down-Regulation; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D000072000:NF-KappaB Inhibitor alpha; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014466:Ultraviolet Rays; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
D020672:I-kappa B Proteins; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C000606204:NFKBIA protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000072000:NF-KappaB Inhibitor alpha; D053148:Caspase 3