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  • Original Paper
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Caspase-9 and Apaf-1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN

Oncogene volume 21, pages 1848–1858 (2002)Cite this article

Abstract

Important roles have been suggested for caspase-8, caspase-9 and Apaf-1 in controlling tumor development and their sensitivity to chemotherapeutic agents. Methylation and deletion of Apaf-1 and CASP8 results in the loss of their expression in melanoma and neuroblastoma, respectively, while CASP9 localization to 1p36.1 suggests it is a good candidate tumor suppressor. The status of CASP9 and Apaf-1 expression in numerous neuroblastoma cell lines with/without amplified MYCN and chromosome 1p36 loss-of-heterozygosity (LOH) was therefore examined to test the hypothesis that one or both of these genes are tumor suppressors in neuroblastoma. Although CASP9 is included in the region encompassing 1p36 LOH in all neuroblastoma cell lines examined, the remaining CASP9 allele(s) express a functional caspase-9 enzyme. Apaf-1 is also expressed in all neuroblastoma tumor cell lines examined. Thus, the CASP9 or Apaf-1 genes do not appear to function as tumor suppressors in MYCN amplified neuroblastomas. However, ∼20% of the neuroblastoma cell lines with methylated CASP8 alleles are also highly resistant to staurosporine (STS)- and radiation-induced cell death, presumably because cytochrome c is not released from mitochondria. This suggests that a second, smaller sub-group of MYCN amplified neuroblastoma tumors exists with defect(s) in apoptotic signaling components upstream of caspase-9 and Apaf-1. Since no consistent differences in Bcl-2, Bcl-xL or Bax expression were seen in the STS- and radiation-resistant neuroblastomas, it suggests that a unique mitochondrial signaling factor(s) is responsible for the defect in cytochrome c release in this sub-group of tumors.

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Acknowledgements

This work was supported by a grant from the NIH (5 RO1 CA67938) to VJ Kidd, by a Cancer Center Support Grant (5 PO1 CA21765) awarded to St Jude Children's Research Hospital, and by the generous support of the American Lebanese Syrian Associated Charities (ALSAC). Dr Xiaodang Wang kindly provided the human caspase-9 polyclonal antiserum.

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  1. Tie Wei

    Present address: Department Experimental Hematology, St. Jude Children's Research Hospital, Memphis, 38105, TN, USA

  2. Tal Teitz and Tie Wei: T Teitz and T Wei contributed equally to this work

Authors and Affiliations

  1. Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, TN, USA

    Tal Teitz, Tie Wei, Dong Liu, Virginia Valentine, Marcus Valentine, Jose Grenet, Jill M Lahti & Vincent J Kidd

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Correspondence to Vincent J Kidd.

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Teitz, T., Wei, T., Liu, D. et al. Caspase-9 and Apaf-1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN. Oncogene 21, 1848–1858 (2002). https://doi.org/10.1038/sj.onc.1205180

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