Basic and translational research has investigated the role of Nm23 in the regulation of tumor metastasis. Ten transfection studies have documented that overexpression of Nm23 in various tumor cell lines resulted in a 50-90% decrease in tumor metastatic potential in vivo. The biochemical mechanism whereby Nm23 suppresses metastatic potential is under investigation. We have previously reported that a histidine dependent protein phosphotransferase activity correlated with Nm23-H1 suppression of tumor cell motility, an aspect of metastasis. We identified a physiologic substrate for Nm23-H1 as a histidine kinase, the Kinase suppressor of ras (Ksr), which is a scaffold protein for the Map kinase pathway. Nm23-H1 phosphorylated serines 392 and 434 of Ksr. Transfection of breast carcinoma cells with wild type Nm23-H1 reduced Map kinase activation as compared to vector transfectant controls. Transfection of a histidine kinase-deficient Nm23-H1 resulted in high Map kinase levels, indicating that the histidine kinase activity of Nm23-H1 is responsible for modulation of signaling. We suggest the hypothesis that Nm23-H1 phosphorylation of Ksr results in altered scaffold function, reduced Map kinase signaling and reduced metastatic potential. Translational research on Nm23 proposes that elevation of Nm23 expression in micrometastatic or overtly metastatic breast or other carcinomas may limit colonization, motility and de-differentiation, with a clinical benefit. Analysis of the nm23-H1 promoter revealed a 400 bp region which controlled expression, and contained a cassette of transcription factors regulated by a glucocorticoid response element (GRE). Deletion studies showed that these sites were functional in regulating nm23-H1 transcription. We now report that Dexamethasone, a Glucocorticoid receptor (GR) agonist, elevated the Nm23-H1 expression of metastatic human breast cancer cell lines in vitro. The activity showed high dose inhibition and extended over only the physiologic range of endogenous corticosteroids. Medroxyprogesterone acetate (MPA), an agonist for GR and progesterone receptor, also elevated Nm23-H1 expression of breast carcinoma cell lines in vitro via the GR, but at doses thought to be pharmacologic. Testing is now underway to determine the effect of MPA on Nm23-H1 expression and metastastic potential in vivo.
NIH ExPorter
NIH ExPorter