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Somatostatin and dopamine receptor expression in lung carcinoma cells and effects of chimeric somatostatin-dopamine molecules on cell proliferation

Diego Ferone,¹ Marica Arvigo,¹ Claudia Semino,¹ Philippe Jaquet,² Alexandru Saveanu,² John E. Taylor,³ Jacques-Pierre Moreau,³ Michael D. Culler,³ Manuela Albertelli,¹ Francesco Minuto,¹ and Antonina Barreca^1,

¹Department of Endocrinological and Metabolic Sciences and Centre for Excellence for Biomedical Research, University of Genova, Genova, Italy; ²Interactions Cellulaires Neuroendocriniennes, Unité Mixte de Recherche 6544, Faculté de Médecine Nord, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche, Marseille Cedex, France; and ³Biomeasure Incorporated/Ipsen, Milford, Massachusetts

Submitted 10 May 2005 ; accepted in final form 21 July 2005

To study somatostatin/dopamine (SS/D) synergy in a human cell system constitutively expressing SS and D receptors (SSR and DR, respectively), 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 by using SS-14 and subtype-selective SS analogs (SSA) and D agonists (DA). Because Calu-6 cells produce insulin-like growth factor (IGF) and IGF-binding protein (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 and 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 was 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 BIM-23A387 (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 because of the induction of SSR/DR dimerization. The Calu-6 cell line, constitutively expressing SSR and DR, provides a suitable model to elucidate the mechanism of action of SSA and DA on regulation of cell growth and to characterize the interaction between SSR and DR.

somatostatin receptors; dopamine receptors; receptor dimerization; growth factors; lung carcinoma

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