Somatostatin and dopamine receptor regulation and effects of a new somatostatin/dopamine chimeric compound on cell proliferation of the human androgen-dependent prostate cancer cell line LNCaP
Marica Arvigo1, Massimiliano Ruscica2, Elena Dozio2, Michael D Culler3, Francesco Minuto1, Marcella Motta2, Paolo Magni2 & Diego Ferone1
The increasing use of somatostatin (SRIF) analogues prompted extensive investigations on SRIF receptor (SSR) in human tumours. Human prostate cancer (PCa) may differentially express SSRs from the normal tissue. Moreover, SSR and dopamine (D) receptors (DR) may interact to form homo- and heterodimers with enhanced functional activity. In the present study, using the human androgen-dependent PCa cell line LNCaP, we investigated: 1) SSR and DR subtype expression in different culture conditions (10% and 2% FBS); 2) the effects of SRIF and of a new SRIF/D chimeric molecules, BIM-23A760, able to bind with high affinity both sst2A and D2R on cell proliferation. LNCaP expressed sst1, sst2A, sst3, sst5, and D1R and D2R subtypes at gene (RT-PCR) and protein (Western blot) level. SSRs and D2R expression was differentially regulated by the culture conditions: sst2A, sst5 and D2R expression was not modified by serum concentration, whereas sst1 and sst3 were inversely correlated to serum concentration. Dose-response studies were performed at 24 and 48 h with a dose range from 10−11 to 10−7 M. SRIF inhibited cell proliferation ([3H]thymidine incorporation) after 24 and 48 h at all doses. The clinically available analogue lanreotide inhibited cell proliferation after 24 and 48 h with a maximum effect at 10−11 M. However, the chimeric BIM-23A760 resulted more potent than lanreotide and significantly inhibited cell proliferation after 24 h at 10−9 M and after 48 h in a dose range from 10−7 to 10−11 M. These data indicate a heterogeneous expression of SSRs and DRs in PCa, depending on the culture conditions and show an enhanced potency of the chimeric BIM-23A760 in inhibiting cell proliferation, suggesting an important role of the dopaminergic pathway in PCa. Hence, LNCaP provides a model to study the interaction between membrane receptors and to further investigate chimeric SRIF/D compounds in human cancer.