It is established that growth factors support neuronal survival through the phosphoinositide 3-kinase (PI3K)/Akt pathway but little is known about factors that inhibit Akt signaling in neurons. Given that the sst2 type somatostatin receptor exerts pro-apoptotic effects in tumor cells by inhibiting PI3K/Akt, we examined whether neuronal sst2 has similar effects. In primary cortical cultures heterozygously expressing a sst2 knockout/lacZ knockin allele, beta-galactosidase staining revealed expression of the sst2 gene in the vast majority of the cultured neurons. Somatostatin was identified in a subpopulation of neurons by immunocytochemistry. Immunoblots showed a strong reduction of Akt phosphorylation at S473 in wild type cultures undergoing stimulation with the sst2 agonist BIM-23244. While the sst2 agonist did not cause neuronal death under control conditions, it promoted hypoxic/ischemic neuronal death in cortical cultures subjected to oxygen/glucose deprivation. Treatment of wild type cultures with the sst2 antagonist BIM-23627 and homozygous deletion of the sst2 gene were protective in this paradigm, suggesting that endogenous somatostatin signals through sst2 during hypoxia/ischemia. In fact, examination of sst2 phosphorylation and sst2 internalization provided evidence for sst2 activation in neurons subjected to oxygen/glucose deprivation. Thus, somatostatin acts as a sensor of hypoxia/ischemia, inhibits Akt activity through sst2 and aggravates hypoxic/ischemic neuronal death. sst2-selective antagonists are proposed as neuroprotectants in stroke.

01 Feb 2014·Molecular and Cellular EndocrinologyQ2 · MEDICINE

Characterization and sub-cellular localization of SS1R, SS2R, and SS5R in human late-stage prostate cancer cells: Effect of mono- and bi-specific somatostatin analogs on cell growth

Q2 · MEDICINE

Article

Author: Ameri, P ; Valenti, L ; Magni, P ; Steffani, L ; Minuto, F ; Ruscica, M ; Culler, M D ; Gatto, F ; Albertelli, M ; Magnaghi, V ; Ferone, D ; Arvigo, M ; Rametta, R

Somatostatin (SST) and SST receptors (SS1R, SS2R, SS3R, SS4R and SS5R) appear to play a significant role in the progression of human prostate cancer (PCa), which is associated with heterogeneity of SSRs expression and specific cell localization as we already demonstrated in the LNCaP cell line, an in vitro model of human androgen-dependent PCa. In this study, PC-3 and DU-145 human castration-resistant PCa cells were found to express all SSRs, while LNCaP expressed all but SS4R. A 48-h treatment with BIM-23244 (SS2R/SS5R) or BIM-23926 (SS1R) SST analogs was more effective in inhibiting cell proliferation, compared to BIM-23120 (SS2R), BIM-23206 (SS5R) and BIM-23704 (SS1R/SS2R). BIM-23926 (SS1R) treatment increased the amount of p21 and decreased phosphorylated (p) ERK1/2. BIM-23244 (SS2R/SS5R) led to p21 increment only in PC-3 cells, and to pERK1/2 reduction in both cell lines. SS1R/SS2R and SS2R/SS5R receptor dimers were natively present on cell membrane and their amount was increased by BIM-23704 (SS1R/SS2R) or BIM-23244 (SS2R/SS5R) treatment, respectively. SS1R, SS2R and SS5R were differently distributed among nuclear, lysosomal and microsomal compartment, according to their different recycling dynamics. These results show that, in PC-3, DU-145 and LNCaP cells, activation of SS1R and SS2R/SS5R leads to relevant antiproliferative effects.

01 Dec 2010·Journal of EndocrinologyQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: D Ferone ; P Magni ; M Ruscica ; E Dozio ; M Motta ; M D Culler ; P Ameri ; F Gatto ; M Albertelli ; F Minuto ; M Arvigo

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.

100 Deals associated with BIM-23244

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Indication	Highest Phase	Country/Location	Organization	Date
Acromegaly	Preclinical	US	Biomeasure, Inc.	-
Acromegaly	Preclinical	FR	Biomeasure, Inc.	-

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