Caspase 8L, a novel inhibitory isoform of caspase 8, is associated with undifferentiated neuroblastoma |
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Authors: | M A Miller B Karacay X Zhu M S O'Dorisio A D Sandler MD |
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Institution: | (1) Departments of Surgery and Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242;(2) Department of Surgery, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA, 52242 |
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Abstract: | Caspase 8 is a key apoptotic factor in the receptor/ligand apoptosis-signaling cascade. Absent caspase 8 expression is shown
to correlate with poor prognosis in neuroblastoma. Paradoxically, the caspase 8 gene can produce as plice variant and novel
inhibitor of itself-caspase 8l. The presence of caspase 8 alone in tumors may not necessarily portend a good prognosis. We
sought to determine whether caspase 8l is present in neuroblastoma and whether over-expression of this protein could inhibit
caspase 8-dependent apoptosis. Six of 6 histologically undifferentiated and 2 of 5 differentiated neuroblastoma tumors expressed
the caspase 8l isoform, whereas caspase 8l was absent in 3 of 3 ganglioneuromas. Seven human neuroblastoma cell lines were
surveyed. Two of the 5 cell lines that expressed caspase 8 also expressed the caspase 8l isoform and both were of a less differentiated
neuronal phenotype. Over-expression of caspase 8l in cell lines afforded protection against TRAIL, but not against etoposide
induced apoptosis. Conversely, blockade of Caspase 8l in cells that express this splice variant made them more sensitive to
apoptosis induced cell death. We demonstrate the caspase 8l isoform is present in neuroblastoma and appears to be associated
with undifferentiated cell lines and tumors. Furthermore, it suppresses caspase 8-dependent apoptosis. |
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Keywords: | apoptosis Caspase 8l TRAIL undifferentiated neuroblastoma |
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