Somatostatin and dopamine receptor interaction in prostate and lung cancer cell lines

Somatostatin (SRIF) analogues and the new SRIF/dopamine chimeric compounds inhibit in vitro proliferation of different cell systems by activating specific cognate membrane receptors. Recent studies on transfected cell lines have shown that SRIF receptors (sstr) can form homo- or hetero-dimers on cell membranes either in basal conditions or after treatment with their ligands. The aim of this study was: 1) to evaluate the role of specific ligands in modulating receptor interaction/dimerization processes 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 methods; 2) to compare and correlate the antiproliferative effect of these compounds with their ability in increasing the amount of co-immunoprecipitated receptors (inducing dimers). LNCaP cells constitutive express sstr1/sstr2, sstr2/sstr5, and sstr5/D2R dimers. BIM-23704, a sstr1-sstr2 preferential compound, increased the amount of sstr1 co-immunoiprecipitated with sstr2 and significantly inhibited cell proliferation by -31%. BIM-23244, a sstr2-sstr5 selective agonist, significantly increased the amount of sstr2 co-immunoprecipitated with sstr5 and inhibited cell proliferation by -41%. BIM-23A760, a SRIF/dopamine chimeric agonist with high affinity for sstr2/D2R and moderate affinity for sstr5, significantly increased the amount of sstr5/D2R heterodimer, resulting the most powerful molecule in inhibiting cell proliferation (-42 %). Compared with the other SRIF analogues, the chimeric compound was more efficient in modulating sstr5/D2R interaction in Calu-6 cells. Indeed, BIM-23A760 significantly increased the amount of D2R co-immunoprecipitated with sstr5 and inhibited cell proliferation by -31%. However, BIM-53097, a D2R preferential compound, resulted also significantly potent in inhibiting Calu-6 cell proliferation (-18%), suggesting a key role of the D2R in receptor cross-talk and in the control of cell growth. In conclusion, a dynamic ligand-induced SRIF and dopamine receptor interaction, probably a receptor dimerization, may be crucial for the antiproliferative effects of the new SRIF analogues and SRIF/dopamine chimeric molecules.