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Submitted on May 27, 2003
Accepted on October 21, 2003
1 Department of Pediatrics, General Hospital Salzburg, Muellner Hauptstrasse 48, A-5020 Salzburg, Austria (A.B., R.L., K.M., R.S., W.S., B.K.); Department of Molecular Neurobiology and Cellular Physiology, Institute of Zoology, University of Salzburg, Hellbrunnerstrasse 34, A-5020 Salzburg, Austria (A.H.)
* To whom correspondence should be addressed. E-mail: b.kofler{at}lks.at.
Recently we have shown that galanin binding significantly correlates with survival in neuroblastoma patients, indicating a possible modulatory role of galanin receptors in neuroblastic tumor biology. However, the molecular mechanisms beyond this correlation have not been elucidated. Here, the cellular effects upon activation of specific galanin receptor subtypes in human SH-SY5Y neuroblastoma cells were analyzed using a tetracycline controlled expression system. Pharmacolocigal studies confirmed the inducible expression of high affinity binding sites for galanin in SH-SY5Y cells transfected with the galanin receptors GalR1 (SY5Y/GalR1) and GalR2 (SY5Y/GalR2). Microphysiometry revealed that both receptor subtypes were able to mediate an intracellular signal upon galanin application. Interestingly, induction of receptor expression and treatment with 100 nM galanin resulted in a dramatic decrease of cell viability in SY5Y/GalR2 cells (93 ± 3%) compared with a less pronounced effect in SY5Y/GalR1 cells (19 ± 10%). The antiproliferative potency of galanin was 100-fold higher in SY5Y/GalR2 (EC50 1.1 nM) than in SY5Y/GalR1 cells (EC50 190 nM). Furthermore, activation of receptor expression and exposure to galanin resulted in apparent morphological changes indicative for apoptosis in SY5Y/GalR2 cells only. Induction of cell death by the apoptotic process was confirmed by Poly-(ADP-ribose)-polymerase (PARP) cleavage, caspase-3 activation and by the typical laddering of DNA. This study indicates that a high level of GalR2 expression is able to inhibit cell proliferation and induce apoptosis in neuroblastoma cells and therefore identifies GalR2 as a possible target for pharmacological intervention in neuroblastoma.
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