Tyr-c[D-Orn-Tyr(Bzl)-Pro-Gly]: a novel antiproliferative acting somatostatin receptor agonist with mu-opioid receptor-sensitizing properties.
(1) Here, we introduce a beta-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 mu-receptors, but enhances the agonist binding to mu-receptors in vitro and potentiates the analgesic effect of morphin in vivo. The molecular mechanism of mu-receptor sensitization by cCD-2 is not yet known. (3) The antiproliferative effect of cCD-2 is independent of mu-, delta-, and kappa-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 mu-receptor affinity but may induce mu-receptor sensitization and is structurally different from the hitherto known SST receptor agonists.
Stirnweiss
Jörg
J
Institute of Biochemistry and Biophysics, Biological and Pharmaceutical Faculty, Friedrich-Schiller-University Jena, Philosophenweg 12, Jena D-07743, Germany.
Hartrodt
Bianka
B
Greksch
Gisela
G
Stürzebecher
Uta
U
Böhmer
Frank-D
FD
Neubert
Klaus
K
Liebmann
Claus
C
D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004723:Endorphins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000378:metabolism
D004723:Endorphins; D006131:Growth Inhibitors; D009292:Narcotic Antagonists; D010446:Peptide Fragments; D017450:Receptors, Opioid, mu; D017481:Receptors, Somatostatin; C034812:beta-casomorphin 5