Survivin inhibits apoptosis induced by TRAIL, and the ratio between survivin and TRAIL receptors is predictive of recurrent disease in neuroblastoma.
OBJECTIVE
Novel treatment strategies for high-risk and disseminated neuroblastoma (NB) are actively sought because of the dismal prognosis of advanced stage disease. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a recently identified member of the tumor necrosis factor family. TRAIL is capable of inducing apoptosis in multiple tumor cell types, with little or no cytotoxicity against normal cells.


METHODS
We examined the activation and regulation of TRAIL-induced apoptosis in several human NB cell lines. The effect of TRAIL was examined in the context of TRAIL receptor (TRAIL-R) and survivin (an antiapoptotic protein) expression in the cell lines. The ratio of survivin/TRAIL-R messenger RNA was determined and evaluated as a marker of recurrent disease in patients with NB.


RESULTS
TRAIL induced apoptotic cell death of NB with variable sensitivities among the cell lines tested. Compared with a sensitive cell line (early passage NB16), the resistant cell lines (NB7 and late passage NB16) expressed lesser amounts of the death-inducing TRAIL-R1 and R2, and greater levels of survivin, an inhibitor of apoptosis. TRAIL sensitivity was enhanced in resistant cell lines by treating with etoposide that concomitantly increased TRAIL-R expression and diminished survivin expression. Survivin overexpression in a TRAIL-sensitive NB line (early passage NB16) rendered it less sensitive to treatment with TRAIL. Conversely, inhibiting survivin expression in NB3 by antisense oligonucleotides enhanced TRAIL sensitivity. A high survivin/TRAIL-R ratio accurately predicted risk for recurrent disease in primary tumor specimens tested.


CONCLUSIONS
These findings suggest that TRAIL therapy in combination with specific chemotherapeutic agents may represent an effective therapeutic strategy for NB. The cell's sensitivity to TRAIL is at least partially governed by both TRAIL-R and survivin expression, whereas the ratio between these 2 factors appears to have prognostic value in patients with this disease.
Azuhata
Takeo
T
First Department of Surgery, Nihon University, Tokyo, Japan.
Scott
David
D
Griffith
Thomas S
TS
Miller
Michal
M
Sandler
Anthony D
AD
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002648:Child; D005047:Etoposide / Q000494:pharmacology; D058851:GPI-Linked Proteins; D018305:Ganglioneuroblastoma / Q000378:metabolism; D005729:Ganglioneuroma / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000494:pharmacology*; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma / Q000378:metabolism*; D011237:Predictive Value of Tests; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; D058851:GPI-Linked Proteins; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C108661:TNFRSF10C protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D005047:Etoposide