Resistance and susceptibility of human uveal melanoma cells to TRAIL-induced apoptosis

Objective: To evaluate the resistance and susceptibility of human uveal melanoma cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Methods: The sensitivity of 11 human uveal melanoma cell lines was analyzed by flow cytometry for the expression of TRAIL receptors and the antiapoptotic protein survivin. Caspase-8 and caspase-10 expression was also examined using reverse transcriptase-polymerase chain reaction and Western blot analysis. Results: Only 4 melanoma cell lines were sensitive to TRAIL-induced apoptosis. Positive correlation was observed between resistance and expression of survivin. Upregulation of survivin by gene transfer enhanced resistance to TRAIL-induced apoptosis, whereas transfection with survivin antisense rendered resistant melanoma cells susceptible to TRAIL-induced apoptosis. Survivin expression and susceptibility to TRAIL-induced apoptosis could also be manipulated by treatment with actinomycin D, which produced a 30% to 50% decrease in the expression of survivin (P < .01) and a 5- to-7-fold increase in TRAIL-induced apoptosis (P < .001). Conclusions: Resistance of uveal melanoma cells to TRAIL-induced apoptosis is regulated by antiapoptotic proteins such as survivin. Clinical Relevance: Manipulation of apoptosis regulatory proteins, such as survivin, may have therapeutic applications in the management of uveal melanomas.