Study of the molecular mechanisms responsible of the transition of the prion protein fragment 90-231 in a neurotoxic conformation.

Somatostatin (SST), an peptide expressed in most organs and tissues, and controlling a wide range of physiological activities, is also one of the main endogenous regulators of cell proliferation. Thus, it has been proposed its clinical use in the cancer pharmacological therapy, but the outcome of the trials performed has been largely unsatisfactory. However, in the past few years, a great bulk of novel information about the molecular mechanisms involved in the SST antiproliferative activity have raised again the possibility of its use in the oncological field. Here we described, in the context of the recent literature observations on the transduction mechanisms regulated by SST, the effects of SST on two phosphotyrosine phosphatases (PTP) that in different cellular systems may mediate the growth inhibition of the peptide. First, in a thyroid cell line we identified a receptor-like PTP, named PTP, whose expression is absolutely required for the antiproliferative effects of the peptide. Indeed, in an in vitro model transformed thyroid cells SST is not able to inhibit cell proliferation unless this PTP is expressed. The second PTP involved is SHP-2, a SH2 containing, cytosolic, membrane-bound PTP. In CHO cells expressing SSTR1 the antiproliferative activity of SST is mediated by the activation of MAP kinase through SHP-2 and the induction of the cyclin-dependent kinase inhibitor p21cip1/waf1. Thus, the identification of more precise molecular mechanisms of the SST antiproliferative activity may allow a reconsideration for the clinical use of SST analogues with more selective growth inhibitory activity