Limits...
Neuroblastoma tumorigenesis is regulated through the Nm23-H1/h-Prune C-terminal interaction.

Carotenuto M, Pedone E, Diana D, de Antonellis P, Džeroski S, Marino N, Navas L, Di Dato V, Scoppettuolo MN, Cimmino F, Correale S, Pirone L, Monti SM, Bruder E, Zenko B, Slavkov I, Pastorino F, Ponzoni M, Schulte JH, Schramm A, Eggert A, Westermann F, Arrigoni G, Accordi B, Basso G, Saviano M, Fattorusso R, Zollo M - Sci Rep (2013)

Bottom Line: H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers.We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation.We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP.

View Article: PubMed Central - PubMed

Affiliation: Centro di Ingegneria Genetica e Biotecnologie Avanzate-CEINGE, Naples, Italy.

ABSTRACT
Nm23-H1 is one of the most interesting candidate genes for a relevant role in Neuroblastoma pathogenesis. H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers. Our study focuses on the role of the Nm23-H1/h-Prune protein complex in Neuroblastoma. Using NMR spectroscopy, we performed a conformational analysis of the h-Prune C-terminal to identify the amino acids involved in the interaction with Nm23-H1. We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation. Meta-analysis performed on three Neuroblastoma cohorts showed Nm23-H1 as the gene highly associated to Neuroblastoma aggressiveness. We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP. These data suggest a new avenue for potential clinical application of CPP in Neuroblastoma treatment.

Show MeSH

Related in: MedlinePlus

Status of N-MYC/Nm23-H1 high and h-Prune NBL tumors and a model of action of CPP.(a) Level of phosphorylation of Nm23-H1 and complex formation through the h-Prune C-terminal has prognostic relevance for determining an aggressive NBL phenotype, and thus worse outcome. (b) Use of the mimetic peptide CPP which can impair the binding of Nm23-H1 and h-Prune in vitro and in vivo, resulting in substantial impairment of cell motility and metastatic niche formation in vivo, with therapeutic benefit. This is accompanied by inhibition of the WNT, NF-κb, AKT and FAK intracellular signaling pathways.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3584926&req=5

f7: Status of N-MYC/Nm23-H1 high and h-Prune NBL tumors and a model of action of CPP.(a) Level of phosphorylation of Nm23-H1 and complex formation through the h-Prune C-terminal has prognostic relevance for determining an aggressive NBL phenotype, and thus worse outcome. (b) Use of the mimetic peptide CPP which can impair the binding of Nm23-H1 and h-Prune in vitro and in vivo, resulting in substantial impairment of cell motility and metastatic niche formation in vivo, with therapeutic benefit. This is accompanied by inhibition of the WNT, NF-κb, AKT and FAK intracellular signaling pathways.

Mentions: Here, we represent these findings by the model outlined in Figure 7. Although the exact Nm23-H1 mechanism of action for the mediation of NBL aggressiveness is not completely understood, the data presented here supports the concept that Nm23-H1, through the binding with h-Prune, could act as pro-metastatic gene. In silico data demonstrates that Nm23-H1 was also overexpressed in Th-ALKF117441 and Lin28b37 transgenic mice (Supplementary Fig. 9b). Those results are of importance because CPP was already found impairing the same pathways (Fig. 6), hence arguing its efficacy in future experiments using genetic animal model of NBL.


Neuroblastoma tumorigenesis is regulated through the Nm23-H1/h-Prune C-terminal interaction.

Carotenuto M, Pedone E, Diana D, de Antonellis P, Džeroski S, Marino N, Navas L, Di Dato V, Scoppettuolo MN, Cimmino F, Correale S, Pirone L, Monti SM, Bruder E, Zenko B, Slavkov I, Pastorino F, Ponzoni M, Schulte JH, Schramm A, Eggert A, Westermann F, Arrigoni G, Accordi B, Basso G, Saviano M, Fattorusso R, Zollo M - Sci Rep (2013)

Status of N-MYC/Nm23-H1 high and h-Prune NBL tumors and a model of action of CPP.(a) Level of phosphorylation of Nm23-H1 and complex formation through the h-Prune C-terminal has prognostic relevance for determining an aggressive NBL phenotype, and thus worse outcome. (b) Use of the mimetic peptide CPP which can impair the binding of Nm23-H1 and h-Prune in vitro and in vivo, resulting in substantial impairment of cell motility and metastatic niche formation in vivo, with therapeutic benefit. This is accompanied by inhibition of the WNT, NF-κb, AKT and FAK intracellular signaling pathways.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3584926&req=5

f7: Status of N-MYC/Nm23-H1 high and h-Prune NBL tumors and a model of action of CPP.(a) Level of phosphorylation of Nm23-H1 and complex formation through the h-Prune C-terminal has prognostic relevance for determining an aggressive NBL phenotype, and thus worse outcome. (b) Use of the mimetic peptide CPP which can impair the binding of Nm23-H1 and h-Prune in vitro and in vivo, resulting in substantial impairment of cell motility and metastatic niche formation in vivo, with therapeutic benefit. This is accompanied by inhibition of the WNT, NF-κb, AKT and FAK intracellular signaling pathways.
Mentions: Here, we represent these findings by the model outlined in Figure 7. Although the exact Nm23-H1 mechanism of action for the mediation of NBL aggressiveness is not completely understood, the data presented here supports the concept that Nm23-H1, through the binding with h-Prune, could act as pro-metastatic gene. In silico data demonstrates that Nm23-H1 was also overexpressed in Th-ALKF117441 and Lin28b37 transgenic mice (Supplementary Fig. 9b). Those results are of importance because CPP was already found impairing the same pathways (Fig. 6), hence arguing its efficacy in future experiments using genetic animal model of NBL.

Bottom Line: H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers.We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation.We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP.

View Article: PubMed Central - PubMed

Affiliation: Centro di Ingegneria Genetica e Biotecnologie Avanzate-CEINGE, Naples, Italy.

ABSTRACT
Nm23-H1 is one of the most interesting candidate genes for a relevant role in Neuroblastoma pathogenesis. H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers. Our study focuses on the role of the Nm23-H1/h-Prune protein complex in Neuroblastoma. Using NMR spectroscopy, we performed a conformational analysis of the h-Prune C-terminal to identify the amino acids involved in the interaction with Nm23-H1. We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation. Meta-analysis performed on three Neuroblastoma cohorts showed Nm23-H1 as the gene highly associated to Neuroblastoma aggressiveness. We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP. These data suggest a new avenue for potential clinical application of CPP in Neuroblastoma treatment.

Show MeSH
Related in: MedlinePlus