Abstract
Neuroblastoma (NB) is a malignant tumor deriving from the neural crest and is responsible for 13% of cancer-related deaths in children. Phosphoinositide 3-kinases (PI3Ks) play a central role in NB tumorigenesis. PI3Ks activate AKT, which regulates survival and stabilizes the MYCN oncogene. Both MYCN and AKT are markers for poor prognosis in NBs. Inhibiting PI3Ks with pan-inhibitors blocks malignant progression in vivo; however, these inhibitors have high toxicity that limits their use in NB treatment. Though there are three classes of PI3Ks, only Class I isoforms have been implicated in NB tumorigenesis. We have previously found that the scaffold protein intersectin 1 (ITSN1) interacts with PI3KC2α and regulates its activation as well as AKT activation in neuronal cell lines. In addition, ITSN1 overexpression is transforming in rodent fibroblasts. Thus, we examined the role of the ITSN1-PI3KC2α pathway in human NB tumorigenesis. ITSN1 and PI3KC2α are highly expressed in primary human neuroblastoma tumors of varying stage and MYCN amplification status. In addition, both ITSN1 and PI3KC2α are expressed in NB tumor cell lines derived from high grade NB tumors. Silencing ITSN1 dramatically inhibited the anchorage-independent growth of NB tumor cells in vitro and tumor formation in xenograft assays in vivo independent of MYCN status. Conversely, heterologous overexpression of ITSN1 increased the formation of soft agar colonies. These results suggest that ITSN1 functions as an oncogene in NB cells. Furthermore, PI3KC2α overexpression restores anchorage-independent growth of ITSN1-depleted NB cells demonstrating that PI3KC2α mediates ITSN1's tumorigenic properties. This study reveals a new pathway, i.e., ITSN1-PI3KC2α, involved in regulating the pathogenesis of NBs and suggests that this pathway may represent a new target for therapeutic intervention in the treatment of NB patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3249. doi:1538-7445.AM2012-3249
- ©2012 American Association for Cancer Research
Volume 72, Issue 8 Supplement
