Somatostatin and dopamine receptor interaction in prostate and lung cancer cell lines.
Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors (SSTRs). Recent studies on transfected cell lines have shown a ligand-induced formation of receptor dimers. The aim of this study is 1) to evaluate the role of specific ligands in modulating receptor interactions in the androgen-dependent prostate cancer cell line, LNCaP, and in the non-small cell lung cancer line, Calu-6, by co-immunoprecipitation and immunoblot; and 2) to correlate the antiproliferative effect of these compounds with their ability in modulating receptor interactions. In LNCaP, we have demonstrated the constitutive presence of sstr₁/sstr₂, sstr₂/sstr₅, sstr₅/dopamine (DA) type 2 receptor (D₂R), and sstr₂/D₂R dimers. BIM-23704 (sstr₁- and sstr₂-preferential compound) increased the co-immunoprecipitation of sstr₁/sstr₂ and significantly inhibited proliferation (-30.98%). BIM-23244 (sstr₂-sstr₅ selective agonist) significantly increased the co-immunoprecipitation of sstr₂/sstr₅, and induced a -41.36% inhibition of proliferation. BIM-23A760, a new somatostatin/DA chimeric agonist with a high affinity for sstr₂ and D₂R and a moderate affinity for sstr₅, significantly increased the sstr₅/D₂R and sstr₂/D₂R complexes and was the most powerful in inhibiting proliferation (-42.30%). The chimeric compound was also the most efficient in modulating receptor interaction in Calu-6, increasing the co-immunoprecipitation of D₂R/sstr₅ and inhibiting cell proliferation (-30.54%). However, behind BIM-23A760, BIM-53097 (D₂R-preferential compound) also significantly inhibited Calu-6 proliferation (-17.71%), suggesting a key role for D₂R in receptor cross talk and in controlling cell growth. Indeed, activation of monomeric receptors did not affect receptor co-immunoprecipitation, whereas cell proliferation was significantly inhibited when the receptors were synergistically activated. In conclusion, our data show a dynamic ligand-induced somatostatin and DA receptor interaction, which may be crucial for the antiproliferative effects of the new analogues.
Arvigo
M
M
Department of Endocrinological and Medical Sciences and Center of Excellence for Biomedical Research, Università degli Studi di Genova, 16132 Genova, Italy.
Gatto
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F
Ruscica
M
M
Ameri
P
P
Dozio
E
E
Albertelli
M
M
Culler
M D
MD
Motta
M
M
Minuto
F
F
Magni
P
P
Ferone
D
D
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004298:Dopamine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000032:analysis / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism*; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*
C423390:BIM-23244; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; D013004:Somatostatin; C531242:TBR-760; D004298:Dopamine