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Caspase 8L, a novel inhibitory isoform of caspase 8, is associated with undifferentiated neuroblastoma

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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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Authors and Affiliations

  1. Departments of Surgery and Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242

    M. A. Miller, B. Karacay, X. Zhu, M. S. O'Dorisio & A. D. Sandler MD

  2. Department of Surgery, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA, 52242

    A. D. Sandler MD

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  1. M. A. Miller
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  2. B. Karacay
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  3. X. Zhu
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  4. M. S. O'Dorisio
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  5. A. D. Sandler MD
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Correspondence to A. D. Sandler MD.

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Miller, M.A., Karacay, B., Zhu, X. et al. Caspase 8L, a novel inhibitory isoform of caspase 8, is associated with undifferentiated neuroblastoma. Apoptosis 11, 15–24 (2006). https://doi.org/10.1007/s10495-005-3258-0

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