The activation of type 1 corticotropin releasing factor receptor (CRF-R1) inhibits proliferation and promotes differentiation of neuroblastoma cells in vitro via p27Kip1 protein up-regulation and c-Myc mRNA down-regulation

Our group has previously shown that corticotropin releasing factor (CRF) inhibits\r\nproliferation of human endocrine-related cancer cell lines via the activation of CRF type-1 receptors\r\n(CRF-R1). Tumors originating from the nervous system also express CRF receptors but their role on\r\nneoplastic cell proliferation was poorly investigated. Here we investigated the effect of CRF receptor\r\nstimulation on nervous system-derived cancer cells, using the SK-N-SH (N) human neuroblastoma cell\r\nline as an experimental model. We found that SK-N-SH (N) cells express functionally active CRF-R1,\r\nwhose activation by CRF and the cognate peptide urocortin (UCN) is associated to reduced cell\r\nproliferation and motility, as well as neuronal-like differentiation. UCN did not interfere with cell\r\nviability and cell-cycle arrest. The above effects seem to be mediated by a mechanism involving the\r\nactivation of cAMP/PKA/CREB pathway and the subsequent downstream increase in p27Kip1 and\r\nunderphosphorylated retinoblastoma protein levels, as well as reduced c-Myc mRNA accumulation