This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Li, L. C. Articles by Meriggioli, M. N. PubMed PubMed Citation Articles by Li, L. C. Articles by Meriggioli, M. N.

Regulation of Apoptosis and Caspase-8 Expression in Neuroblastoma Cells by Isoforms of the IG20 Gene

Departments of ¹ Neurology and ² Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois

Requests for reprints: Matthew N. Meriggioli, Neuromuscular Diseases Program, Department of Neurology and Rehabilitation, University of Illinois at Chicago, 912 South Wood Street, 855N, M/C 796, Chicago, IL 60523. Phone: 312-355-1528; Fax: 312-413-3829; E-mail: Mmerig{at}uic.edu.

Key Words: Neuroblastoma • IG20 • KIAA0358 • IG20-SV4 • caspase-8 • apoptosis

The IG20 gene undergoes alternative splicing resulting in the differential expression of six putative splice variants. Four of these (IG20pa, MADD, IG20-SV2, and DENN-SV) are expressed in virtually all human tissues. However, investigations examining alternative splicing of the IG20 gene to date have been largely limited to nonneural malignant and nonmalignant cells. In this study, we investigated the expression of alternative splice isoforms of the IG20 gene in human neuroblastoma cells. We found that six IG20 splice variants (IG20-SVs) were expressed in two human neuroblastoma cell lines (SK-N-SH and SH-SY5Y), highlighted by the expression of two unique splice isoforms (i.e., KIAA0358 and IG20-SV4). Similarly, we found enriched expression of these two IG20-SVs in human neural tissues derived from cerebral cortex, hippocampus, and, to a lesser extent, spinal cord. Using gain-of-function studies and siRNA technology, we determined that these "neural-enriched isoforms" exerted significant and contrasting effects on vulnerability to apoptosis in neuroblastoma cells. Specifically, expression of KIAA0358 exerted a potent antiapoptotic effect in both the SK-N-SH and SH-SY5Y neuroblastoma cell lines, whereas expression of IG20-SV4 had proapoptotic effects directly related to the activation of caspase-8 in these cells, which have minimal or absent constitutive caspase-8 expression. These data indicate that the pattern of expression of these neural-enriched IG20-SVs regulates the expression and activation of caspase-8 in certain neuroblastoma cells, and that manipulation of IG20-SV expression pattern may represent a potent therapeutic strategy in the therapy of neuroblastoma and perhaps other cancers. [Cancer Res 2008;68(18):7352–61]