The effects of s analgus RC-160and SMS-201-995 on tyrosine phosphatase and cell proliferation were investigated in COS-7 and NIH 3T3 cells expressing human somatostatin receptor subtype 1 or 2 (SSTR1 or SSTR2 antagonize the mitogenic effect of growth factors acting on tyrosine kinase receptors such as epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) (9-11). Furthermore, these analogues have been found to stimulate tyrosine phosphatase activity in normal and tumoral pancreatic cells (9,(12)(13)(14)(15) and to activate the dephosphorylation of EGF receptor (9, 16). The ability of somatostatin analogues to stimulate tyrosine phosphatase correlates with their inhibitory effect on pancreatic cell growth, and this correlation supports the hypothesis that the growth inhibition is mediated by dephosphorylation of tyrosine protein signals. Somatostatin analogues might suppress tumor growth by reversing the stimulatory effect of EGF on phosphorylation of EGF receptor tyrosine kinase and EGF-phosphorylated proteins (17). We also observed that a membrane tyrosine phosphatase is coeluted with somatostatin receptor, suggesting that tyrosine phosphatase may be a part ofthe signal transduction pathway promoted by somatostatin receptor occupancy (16).The somatostatin receptor subtypes and the molecular mechanism involved in the tyrosine phosphatase stimulation have been, until now, unknown (18, 19). We must better understand what physiological response every subtype elicits, how their signals are processed in the cell, and in what normal and/or pathological tissues each is expressed to choose the appropriate analogue for targeting to specific cells for therapeutic use.In the present study, we examined the effects of two somatostatin analogues, RC-160 and SMS, on binding and signal transduction pathways of the two human cloned somatostatin receptor subtypes hSSTR1 and hSSTR2 transiently expressed in COS-7 cells. We also investigated the 2315The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Therapeutic strategies using drugs which cause Lysosomal Cell Death have been proposed for eradication of resistant cancer cells. In this context, nanotherapy based on Magnetic Intra-Lysosomal Hyperthermia (MILH) generated by magnetic nanoparticles (MNPs) that are grafted with ligands of receptors overexpressed in tumors appears to be a very promising therapeutic option. However, mechanisms whereby MILH induces cell death are still elusive. Herein, using Gastrin-grafted MNPs specifically delivered to lysosomes of tumor cells from different cancers, we provide evidences that MILH causes cell death through a non-apoptotic signaling pathway. The mechanism of cell death involves a local temperature elevation at the nanoparticle periphery which enhances the production of reactive oxygen species through the lysosomal Fenton reaction. Subsequently, MILH induces lipid peroxidation, lysosomal membrane permeabilization and leakage of lysosomal enzymes into the cytosol, including Cathepsin-B which activates Caspase-1 but not apoptotic Caspase-3. These data highlight the clear potential of MILH for the eradication of tumors overexpressing receptors.