Tyr-c[D-Orn-Tyr(Bzl)-Pro-Gly]: A novel antiproliferative acting somatostatin receptor agonist with μ-opioid receptor-sensitizing properties

Abstract

1. Here, we introduce a β-casomorphin-5-derived cyclic pentapeptide, cCD-2 (Tyr-cyclo[D-Orn-Tyr(Bzl)-Pro-Gly]), which inhibits the cell growth of a variety of human cancer cell lines. 2. This opioid-derived peptide possesses only low affinity for μ-receptors, but enhances the agonist binding to μ-receptors in vitro and potentiates the analgesic effect of morphin in vivo. The molecular mechanism of μ-receptor sensitization by cCD-2 is not yet known. 3. The antiproliferative effect of cCD-2 is independent of μ-, δ-, and κ-receptors. 4. Using SH-SY5Y cells as model, we can demonstrate that cCD-2 specifically binds to somatostatin receptors and stimulates the activity of protein tyrosine phosphatases, which are early downstream targets of SST receptors. 5. In SH-SY5Y cells, cCD-2 specifically increases the activity of the cytosolic PTP SHP-2, stimulates the activity of mitogen-activated protein kinase (MAPK), and elevates the expression of the cyclin-dependent kinase inhibitor p21 (WAF1/Cip1), suggesting the involvement of SSTR1 receptor subtype in cCD-2 action in this cell type. 6. In COS-7 cells, for comparison, we found a stimulation of SHP-2 as well as SHP-1 in response to cCD-2. The activation of SHP-1, which is attributed to the SSTR2 receptor and negatively regulates the EGF receptor, corresponds with the ability of cCD-2 to inhibit the EGF-induced MAPK activation in COS-7 cells. 7. Our results show that in SH-SY5Y cells cCD-2 inhibits cell growth via the SSTR1 receptor-signalling pathway but may, in other cells, also use other SSTR subtypes and their signalling mechanisms. 8. cCD-2 represents a novel type of opioid-derived antiproliferative SST receptor agonist, which possesses low μ-receptor affinity but may induce μ-receptor sensitization and is structurally different from the hitherto known SST receptor agonists.