Somatostatin and dopamine receptor expression in lung carcinoma cells and effects of chimeric somatostatin-dopamine molecules on cell proliferation.
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 sst(2) and D(2)R, 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 sst(2) and the long isoform of the D(2)R were detected by real-time RT-PCR and Western blot in Calu-6, together with sst(5) and to a lesser extent sst(3) and D(4)R. 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 [(3)H]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.
Ferone
Diego
D
Dept. of Endocrinological & Metabolic Sciences, University of Genoa, Viale Benedetto XV 6, 16132-Genoa, Italy. ferone@unige.it
Arvigo
Marica
M
Semino
Claudia
C
Jaquet
Philippe
P
Saveanu
Alexandru
A
Taylor
John E
JE
Moreau
Jacques-Pierre
JP
Culler
Michael D
MD
Albertelli
Manuela
M
Minuto
Francesco
F
Barreca
Antonina
A
D000172:Acromegaly; D000077465:Cabergoline; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004298:Dopamine / Q000494:pharmacology*; D004873:Ergolines / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010911:Pituitary Neoplasms / Q000737:chemistry; D012333:RNA, Messenger / Q000032:analysis; D011954:Receptors, Dopamine / Q000235:genetics* / Q000502:physiology; D017481:Receptors, Somatostatin / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology*
D004873:Ergolines; D018971:Insulin-Like Growth Factor Binding Protein 2; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D017481:Receptors, Somatostatin; D011993:Recombinant Fusion Proteins; C060347:lanreotide; D013004:Somatostatin; D007335:Insulin-Like Growth Factor II; D000077465:Cabergoline; D004298:Dopamine