Neuroblastomas are the most common extra-cranial tumors of early childhood. They are biologically heterogeneous tumors with some tumors undergoing spontaneous regression or differentiation, while a majority have aggressive growth with metastasis and are resistant to multimodal therapy. Less than 20% of patients with advanced disease will survive. Increased telomerase activity is emerging as a prognostic factor in neuroblastoma, associated with advanced stage, MYCN amplification and poor outcome. The MYCN gene encodes for a nuclear phosphoprotein with functional and sequence homology to c-myc. Retinoic acid induces differentiation, growth arrest, apoptosis, and modulates expression of numerous genes in neuroblastoma cell lines. Multiple cellular mechanisms are activated, including the generation of the sphingolipid second messenger ceramide. Ceramide mediates important cellular activities such as induction of cell differentiation, growth arrest, senescence, and apoptosis. Recent studies from the mentors' group have demonstrated the ability of ceramide to inhibit telomerase in lung adenocarcinoma cells. Our preliminary results demonstrate the inhibition of telomerase by retinoic acid in neuroblastoma. Ceramides have been shown to be involved in the differentiation of murine neuroblastoma cell lines in vitro. However, the role of ceramide in retinoic acid induced differentiation and apoptosis in human neuroblastoma cells has not been well characterized. The hypothesis of this proposal is that ceramide mediates the dramatic effects of retinoic acid on cell growth and differentiation in neuroblastoma, and inhibits telomerase activity. Modulating cellular ceramide levels will have profound therapeutic implications. The project's specific aims will: 1) Determine whether the generation of endogenous ceramide is necessary and/or sufficient to induce differentiation of neuroblastoma. 2) Determine the molecular mechanisms and signaling pathways by which ceramide mediates differentiation in human neuroblastoma. 3) Determine if retinoic acid mediated telomerase inhibition is due to ceramide, and determine the molecular mechanisms and signaling pathways involved. The long-term goal of this project is to develop novel therapeutic strategies for the treatment of neuroblastoma.
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