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Neuroblastoma: inhibition of progression (Part II). Basic science in pediatric surgery
R Girgert1, J Wittrock, P Schweizer
1Department of Pediatric Surgery, University of Tübingen, Germany. rainer.girgert@medizin.uni-ulm.de
Abstract:
In neuroblastoma, amplification of the protooncogene N-myc is the most important molecular characteristic predicting a bad outcome for the patients. Despite the importance of the N-myc gene, little is known about the mechanisms regulating its expression. We found evidence that insulin-like growth factor II stimulates the growth of neuroblastoma in a paracrine fashion. Two neuroblastoma cell lines predominantly expressed IGF-II whereas two other cell lines expressed the IGF-receptor. In a receptor-positive cell line, N-myc expression was enhanced by stimulation with IGF-II. As the growth-stimulating signals of the IGF receptor are transmitted via Ras proteins, inactivation of Ras is one promising tool to prevent the induction of N-myc expression by IGF-II. Treatment of neuroblastoma cells with an inhibitor of the farnesyl-protein-transferase (FPTase) inactivated H-ras protein completely and N-ras protein by more than 50 %. Cell growth of neuroblastoma cells in serum containing medium was clearly diminished by inhibition of FPTase. The growth-promoting effect of IGF-II was reduced to exactly half the amount observed in non-inhibited cells.
Insights
Insulin-like growth factor II (IGF-II) promotes neuroblastoma growth by increasing N-myc expression. Farnesyl-protein transferase (FPTase) inhibitors reduce this growth and N-myc induction by blocking Ras signaling.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Neuroblastoma is a pediatric cancer where N-myc gene amplification predicts poor patient outcomes.
- Mechanisms regulating N-myc expression, crucial for neuroblastoma progression, are not fully understood.
- Insulin-like growth factor II (IGF-II) has been implicated in promoting neuroblastoma growth.
Purpose of the Study:
- To investigate the role of IGF-II in regulating N-myc expression in neuroblastoma.
- To explore the potential of inhibiting Ras signaling pathways to counteract IGF-II-mediated N-myc induction and tumor growth.
Main Methods:
- Utilized neuroblastoma cell lines with varying expression of IGF-II and IGF-receptor.
- Stimulated receptor-positive cell lines with IGF-II to assess N-myc expression changes.
- Treated cells with a farnesyl-protein transferase (FPTase) inhibitor to evaluate Ras protein inactivation and its effect on cell growth and IGF-II response.
Main Results:
- IGF-II stimulation enhanced N-myc expression in neuroblastoma cells expressing the IGF-receptor.
- FPTase inhibition led to complete inactivation of H-ras and significant inactivation of N-ras proteins.
- FPTase inhibition diminished neuroblastoma cell growth and reduced the growth-promoting effect of IGF-II by 50%.
Conclusions:
- IGF-II promotes neuroblastoma cell growth and N-myc expression, likely via the Ras signaling pathway.
- Inhibition of FPTase represents a potential therapeutic strategy to reduce neuroblastoma proliferation by targeting Ras signaling and mitigating IGF-II effects.