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 apopt osis-inducing ligand (TRAIL) could induce varying degrees of apoptosis in a pproximately two-thirds of human melanoma lines. In the present study, we h ave examined the sensitivity of fresh isolates and early passages of melano ma cells to TRAIL-induced apoptosis from eight patients. We found that fres h isolates were relatively resistant to TRAIL-induced apoptosis and that th is appeared to be associated with low TRAIL death receptor (TRAIL-R) expres sion. TRAIL-R expression was also undetectable in tissue sections from the same melanoma, We attempted to create a model for these findings by generat ion of TRAIL-resistant melanoma lines from TRAIL-sensitive lines grown for prolonged periods in TRAIL, The resulting TRAIL-resistant melanoma cell lin es had low TRAIL-R expression, and sensitivity to TRAIL was increased-rapid ly by pretreatment with proteasome inhibitors known to inhibit activation o f nuclear factor-kappaB. However, the latter treatment had no significant e ffect on the sensitivity of fresh isolates to TRAIL. The levels of the inhi bitors 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 determinan t of resistance of fresh isolates to TRAIL, and the basis for this requires further investigation.