Moreover, blockage of the Nm23-H1/h-Prune interaction with a competitive permeable peptide (CPP) attenuates migration of breast and neuroblastoma cells.
While in breast cancer, NM23-H1 overexpression indicates a benign status through impairing progression of disease, its function is opposite in other cancers; e.g., neuroblastoma.
On the contrary, high levels of nm23 gene expression are noted in the advanced stage of thyroid carcinomas and associated with significant reductions in survival for neuroblastoma and osteosarcoma patients.
However, the k-pn type proline-96 to serine (P96S) and neuroblastoma type serine-120 to glycine (S120G) mutations of Nm23-H1 abrogated its inhibitory activity on colonization and invasion.
Our findings suggest that nm23-H1 and nm23-H2 expression is increased by 17q gain in neuroblastoma and can be further up-regulated by myc overexpression.
Prune protein interacts with the metastasis suppressor nm23-H1, but shows impaired affinity towards the nm23-H1S120G mutant associated with advanced neuroblastoma.
Our findings suggest that differentiation associated functions of nm23 proteins in IMR-32 neuroblastoma cells are carried out by bound nm23-1 proteins docked in a limited number of nm23-1 specific sites.
Moreover, like the Killer-of-prune mutation in Drosophila NDK and the neuroblastoma Ser120 --> Gly mutation in human NDK-A/Nm23-H1, the Ser122 --> Pro substitution in NDK-B affects the stability of the protein toward heat and urea.
Since nm23 gene family members have been proposed to play a role in cellular differentiation, as well as in metastasis suppression, we investigated whether and how DR-nm23, a recently identified third member of the human nm23 gene family, might be involved in neuroblastoma differentiation.
MDA-MB-435 human breast carcinoma cells were transfected with a control expression vector (pCMVBamneo), the vector containing the wild type nm23-H1, or the nm23-H1 vector encoding mutations at the following amino acids: serine 44, a phosphorylation site; proline 96, the k-pn mutation in the Drosophila nm23 homolog that causes developmental defects; histidine 118, involved in Nm23's nucleoside diphosphate kinase activity; and serine 120, a site of mutation in human neuroblastomas and phosphorylation.
Thus, ovarian carcinoma seems to belong to the group of tumours, like colon carcinoma and neuroblastoma, in which nm23 overexpression is associated with a more malignant phenotype.
However, in colorectal carcinoma and neuroblastoma, increased levels of nm23 H1 nucleoside diphosphate kinase A (NDPKA) mRNA are associated with tumorigenesis.
A similar ser120-gly mutation in NME1 has been found in human neuroblastoma, suggesting that mutation in this region may be a general phenomenon related to tumor progression.
Elevated neuroblastomanm23 RNA levels were associated with significant reductions in patient survival in the overall (n = 75) and N-myc non-amplified (n = 61) portion of the cohort.
Our findings indicate that, in contrast to a proposed role for nm23-H1 as a tumor metastasis suppressor, increased p19/nm23 protein in neuroblastoma is correlated with features of the disease that are associated with aggressive tumors.