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1 Department of Endocrinological & Metabolic Sciences and Centre for Excellence for Biomedical Research, University of Genova, Genova, Italy
2 Interactions Cellulaires Neuroendocriniennes, Unite Mixte de Recherche 6544, Centre National de la Recherche Scientifique, Institut Federatif Jean Roche, Faculte de Medecine Nord, Marseille Cedex, France
3 Biomeasure Inc./IPSEN, Milford, Massachusetts, USA
* To whom correspondence should be addressed. E-mail: ferone{at}unige.it.
To study somatostatin/dopamine (SS/D) synergy in a human cell system constitutively expressing SS and D receptors (SSR, DR), we characterized the expression of SSR and DR subtypes in the non-small cell lung cancer line CALU-6 and then we evaluated the effect on cell proliferation of SS/D chimeric molecules (BIM-23A387 and BIM-23A370), which bind with high affinity both sst2 and D2R, and compared the results with those obtained using SS-14 and subtype-selective SS analogs (SSA) and D agonists (DA). Since CALU-6 cells produce IGF and IGFBP peptides, which play a role in the autocrine/paracrine control of cell growth, we also investigated the effects of chimeric compounds on secretion and expression of IGF system components. Relative high levels of sst2, as well as the long isoform of the D2R were detected by real-time RT-PCR and Western blot in CALU-6, together with sst5 and to a lesser extent sst3 and D4R. BIM-23A387 and BIM-23A370 significantly inhibited growth of CALU-6, whereas IGF-IGFBP secretion or expression were unaffected, suggesting a direct inhibitory effect. The inhibition of cell growth, measured by both 3H-thymidine incorporation and cell count, was significantly lower when individual SSA and DA control peptides, or subtype-specific SSA and DA were tested. BIM-23A370 was more potent than BIM23A387 (p<0.001). These findings show that SS/D chimeras can inhibit CALU-6 proliferation in an IGF-independent manner, and suggest that this enhanced potency might be due the induction of SSR/DR dimerization. CALU-6 cell line, constitutively expressing SSR and DR, provides a suitable model to elucidate the mechanism of action of SSA and DA upon regulation of cell growth, and to characterize the interaction between SSR and DR.
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