The role of nm23 in the regulation of tumor metastasis has been investigated. Transfection of human nm23-H1 cDNA into the human MDA-MB- 435 breast carcinoma cell line reduced the in vivo metastatic potential of this cell line by 50-90%. The nm23-H1 transfectants exhibited less colonization potential in soft agar, and reduced motility responses to serum, IGF or PDGF in vitro. The data establish the metastasis suppressive activity of the human nm23-H1 gene in a human breast tumor cell line. Two studies have indicated that Nm23 is involved in the normal differentiation process. Immunohistochemical evaluation of NM23 expression indicated its increased expression coincident with the functional differentiation of the murine heart, nervous system and most epithelial tissues in embryogenesis. In vitro analysis of control and nm23-H1 transfected MDA-MB-435 cell lines indicates that nm23-H1 can directly induce certain aspects of the structural and functional differentiation of normal mammary ducts. A novel biochemical function has been identified for NM23 protein based on a novel serine phosphorylation as a cAMP regulated ATPase. Examination of control and nm23-1 transfected murine melanoma cell lines indicates that the serine phosphorylation of NM23 is directly correlated with nm23-1 suppression of metastasis, while the previously identified nucleoside diphosphate kinase activity of NM23 was not. NM23 transfectants in murine melanoma, human breast carcinoma and human ovarian carcinoma cell lines were more sensitive to the growth inhibitory effects of cisplatin than were control transfectants. Cisplatin inhibited metastasis formation of nm23-1 transfected murine melanoma cells in vivo to a greater extent than control transfectants. The data indicate the potential use of NM23 expression to reduced metastatic colonization and improve chemotherapeutic efficacy.
