Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1783, Issue 6, Pages 1055-1067Publisher
ELSEVIER
DOI: 10.1016/j.bbamcr.2008.02.007
Keywords
caspase-8; neuroblastoma; medulloblastoma; small cell lung carcinoma; retinoid; retinoic acid; CREB; apoptosis; transcription
Categories
Funding
- NCI NIH HHS [P30 CA021765-29S3, P30CA021765, P30 CA021765, R01CA067938, R01 CA067938, R01 CA067938-11] Funding Source: Medline
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Caspase-8 is frequently deleted or silenced in neuroblastoma and other solid tumor such as medulloblastoma and small cell lung carcinoma. Caspase-8 expression can be re-established in neuroblastoma cell lines by treatment with demethylating agents or with IFN-gamma. Here we show that four different retinoic acid (RA) derivatives also increase caspase-8 protein expression in neuroblastoma, medulloblastoma and small cell lung carcinoma cell lines. This increase in protein expression is mirrored by an increase in RNA expression in NB cells. However, the promoter region of the caspase-8 gene was not responsible for the induction of caspase-8 expression. Rather, we identified another intronic region containing a CREB binding site that was required for maximal induction of caspase-8 via RA. DNA-protein interaction assays revealed increased phospho-CREB binding to this response element in RA-treated NB cells. Furthermore, mutations of the CREB binding site completely blocked caspase-8 induction in the luciferase reporter system assay and transfection of dominant-negative form of CREB repressed the up-regulation of caspase-8 by RA. Importantly, RA-released cells maintained caspase-8 expression for at least 2-5 days and were more sensitive to doxorubicin and TNF alpha. Thus, RA treatment in conjunction with TNF alpha and/or subsets of cytotoxic agents may have therapeutic benefits. (C) 2008 Elsevier B.V. All rights reserved.
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