Somatostatin Receptor sst2 Decreases Cell Viability and Hormonal Hypersecretion and Reverses Octreotide Resistance of Human Pituitary Adenomas

Abstract

In human somatotroph adenomas, growth hormone (GH) hypersecretion can be inhibited by somatostatin analogues such as octreotide. Unfortunately, serum GH levels reach normal values in only 60% of treated patients. The decreased sensitivity to octreotide is strongly related to a lower expression of somatostatin receptor sst2. In this present study, the sst2 gene was transferred by an adenoviral vector (Ad-sst2) in human somatotroph (n = 7) and lactotroph (n = 2) adenomas in vitro. Sst2 mRNA levels and sst2 immunostaining dramatically increased after infection. Ten days after infection at 20 multiplicity of infection (MOI), sst2 gene transfer decreased cell viability from 19% to 90% by caspase-dependent apoptosis. At low viral doses (5 MOI), Ad-sst2 decreased GH or prolactin (PRL) basal secretion and mRNA expression. Somatotroph tumors were classified in three groups according to their octreotide sensitivity. Four days after infection by 5 MOI Ad-sst2, the maximal GH suppression by octreotide increased from 31% to 57% in the octreotide partially resistant group and from 0% to 27% in the resistant ones. In the octreotide-sensitive group, EC 50 values significantly decreased from 1.3 Â 10 À11 to 6.6 Â 10 À13 mol/L without improving maximal GH suppression. Finally, lactotroph tumors, nonresponding to octreotide in basal conditions, became octreotide sensitive with a maximal PRL suppression of 43% at 10 À8 mol/L. Therefore, sst2 reexpression is able to improve octreotide sensitivity. Sst2 gene transfer may open new theapeutic strategies in treatment combined with somatostatin analogues.

DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours

“…The qualitative analysis (presence/absence of sst vs presence/absence of a positive response to each of the SSA) confirmed a correlation between sst2 receptor expression at the protein level and the GH-lowering effect of Octreotide, as has also been demonstrated by others (26,58). A semi-quantitative (expression of sst quantified by IRS vs per cent decline of the GH concentration for each SSA) analysis revealed a negative correlation of the IRS for sst2 and the per cent GH decline induced by Octreotide.…”

Human somatostatin receptor-3 distinctively induces apoptosis in MCF-7 and cell cycle arrest in MDA-MB-231 breast cancer cells

“…SSTRs are perceived to act as endogenous tumor suppressors and the prominent receptor subtypes associated with apoptosis include SSTR2 and SSTR3 (He et al, 2009, Sharma et al, 1996, Acunzo et al, 2008, Vernejoul et al, 2002, Guillermet et al, 2003, Bousquet et al, 2006, Ferrante et al, 2006. The lack of SSTRs membrane expression at the tumor indicates the possible failure of SST effect in tumors.…”

“…(War et al, 2011, Hukovic et al, 1996. The appropriate density of membrane bound SSTRs contributes to the sensitivity and effectiveness of in vivo peptide-targeted therapy for somatotroph adenomas (Daly et al, 2006, Acunzo et al, 2008. Also, a longer relapseAbbreviations: EGF, Epidermal growth factor; ERK, Extracellular signal-regulated kinase; EST, 17b-estradiol; GPCRs, G protein-coupled receptors; HA, Hemagglutinin; MAPK, Mitogen-activated protein kinase; MTT, (3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide); PARP-1, Poly (ADP-ribose) polymerase-1; PBS, Phosphate buffered saline; PI3K, Phosphatidylinositol 3-kinase; PTP-1C, Protein tyrosine phosphatase-1C; SST, Somatostatin; SSTR, Somatostatin receptor; TUNEL, Terminal deoxynucleotidyl transferase dUTP nick end labeling.…”

Acromegaly pathogenesis and treatment

“…Clinical octreotide efficacy is predicted by tumor SSTR 2 expression (101, S31). Furthermore, SSTR2 gene transfer enhances octreotide responsiveness in resistant GH adenoma cells (102). In patients treated for at least six months (103-106, S32, S33) and using random fasting GH levels of less than 2.5 μg/l and/or normalization of age-matched IGF1 levels as efficacy markers, approximately 65% of patients treated with octreotide LAR achieved control of GH secretion.…”