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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Hartrodt, Bianka Böhmer, Frank-d Stürzebecher, Uta Stirnweiss, Jörg Greksch, Gisela Neubert, Klaus Liebmann, Claus |
| Description | Author Affiliation: Stirnweiss J ( Institute of Biochemistry and Biophysics, Biological and Pharmaceutical Faculty, Friedrich-Schiller-University Jena, Philosophenweg 12, Jena D-07743, Germany.) |
| Abstract | (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. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 1 |
| Volume Number | 140 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2003-09-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Endorphins Pharmacology Growth Inhibitors Peptide Fragments Receptors, Opioid, Mu Metabolism Receptors, Somatostatin Agonists Cell Division Drug Effects Physiology Cell Line, Tumor Dose-Response Relationship, Drug Chemistry Narcotic Antagonists Pain Measurement Antagonists & Inhibitors Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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