Resistance and Susceptibility of Human Uveal Melanoma Cells to TRAIL-Induced Apoptosis
Haochuan Li, MD;
Jerry Y. Niederkorn, PhD;
Sudha Neelam, MS;
Hassan Alizadeh, PhD
Arch Ophthalmol. 2005;123:654-661.
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. Up-regulation 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.
Author Affiliations: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas.
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