Relative resistance of fresh isolates of melanoma to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.
In previous studies, we have shown that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) could induce varying degrees of apoptosis in approximately two-thirds of human melanoma lines. In the present study, we have examined the sensitivity of fresh isolates and early passages of melanoma cells to TRAIL-induced apoptosis from eight patients. We found that fresh isolates were relatively resistant to TRAIL-induced apoptosis and that this appeared to be associated with low TRAIL death receptor (TRAIL-R) expression. TRAIL-R expression was also undetectable in tissue sections from the same melanoma. We attempted to create a model for these findings by generation of TRAIL-resistant melanoma lines from TRAIL-sensitive lines grown for prolonged periods in TRAIL. The resulting TRAIL-resistant melanoma cell lines had low TRAIL-R expression, and sensitivity to TRAIL was increased rapidly by pretreatment with proteasome inhibitors known to inhibit activation of nuclear factor-kappaB. However, the latter treatment had no significant effect on the sensitivity of fresh isolates to TRAIL. The levels of the inhibitors of apoptosis, Flice-like inhibitory protein and Bcl-2, also did not relate to resistance to TRAIL-induced apoptosis. These results suggest that down-regulation of TRAIL-R on melanoma cells may be the primary determinant of resistance of fresh isolates to TRAIL, and the basis for this requires further investigation.
Nguyen
T
T
Oncology and Immunology Unit, Newcastle Mater Hospital, Newcastle, New South Wales, Australia.
Zhang
X D
XD
Hersey
P
P
D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000096:biosynthesis; D018929:Cell Culture Techniques; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010455:Peptides / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha