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. 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.


CONCLUSIONS
Manipulation of apoptosis regulatory proteins, such as survivin, may have therapeutic applications in the management of uveal melanomas.
Li
Haochuan
H
Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9057, USA.
Niederkorn
Jerry Y
JY
Neelam
Sudha
S
Alizadeh
Hassan
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins; D012333:RNA, Messenger / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014604:Uveal Neoplasms / Q000378:metabolism / Q000473:pathology*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C505530:CASP8 protein, human; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases; C506438:CASP10 protein, human