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

Abstract

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 sstr 1 /sstr 2 , sstr 2 /sstr 5 , sstr 5 /dopamine (DA) type 2 receptor (D 2 R), and sstr 2 /D 2 R dimers. BIM-23704 (sstr 1 -and sstr 2 -preferential compound) increased the co-immunoprecipitation of sstr 1 /sstr 2 and significantly inhibited proliferation (K30 . 98%). BIM-23244 (sstr 2 -sstr 5 selective agonist) significantly increased the co-immunoprecipitation of sstr 2 /sstr 5 , and induced a K41 . 36% inhibition of proliferation. BIM-23A760, a new somatostatin/DA chimeric agonist with a high affinity for sstr 2 and D 2 R and a moderate affinity for sstr 5 , significantly increased the sstr 5 /D 2 R and sstr 2 /D 2 R complexes and was the most powerful in inhibiting proliferation (K42 . 30%). The chimeric compound was also the most efficient in modulating receptor interaction in Calu-6, increasing the co-immunoprecipitation of D 2 R/sstr 5 and inhibiting cell proliferation (K30 . 54%). However, behind BIM-23A760, BIM-53097 (D 2 R-preferential compound) also significantly inhibited Calu-6 proliferation (K17 . 71%), suggesting a key role for D 2 R 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.

Peptide Receptor Targeting in Cancer: The Somatostatin Paradigm

“…These results were confirmed in non-endocrine tumor cells, natively expressing SST receptors and D2R. It was shown that these receptors can interact in the absence of agonists [55] and the treatment with the chimeric compound targeting both receptor types (BIM-23A760) significantly increased the sst5/D2R and sst2/D2R dimers. …”

Somatostatin analogs and chimeric somatostatin–dopamine molecules differentially regulate human growth hormone and prolactin gene expression and secretion in vitro

“…However, these results were obtained in non-pituitary cell lines (CHO or HEK293) stably expressing exogenous receptors, and there is so far no evidence for receptor dimerization in pituitary cells. Recently, somatostatin and D 2 receptors interaction has been demonstrated in prostate cancer cell line, LNCaP, and in non-small cell lung cancer line, Calu-6 (Arvigo et al, 2010). Postreceptor mechanisms involved in the enhanced potency following receptor dimer activation have not yet been characterized.…”

Repurposing the Antipsychotic Trifluoperazine as an Antimetastasis Agent

“…Over the past several years, evidence that dopamine receptors are expressed in cancer cells outside the nervous system has been increasing. DRD2 expression has been found in abnormally proliferating Jurkat cells, prostate cancer lines (LnCAP), and lung cancer stem cells (Arvigo et al, 2010;Basu et al, 2010;Yeh et al, 2012).…”