Dopamine receptor type 2 (
            DRD2
            ) and somatostatin receptor type 2 (
            SSTR2
            ) agonists are effective in inhibiting proliferation of progenitor/stem‐like cells isolated from nonfunctioning pituitary tumors

Abstract Dopamine receptor type 2 (DRD2) agonists are the first-choice treatment for PRL-secreting pituitary tumors but are poorly effective in non-functioning pituitary neuroendocrine tumors (NF-PitNETs). DRD2 reduces AKT phosphorylation in lactotrophs, but no data are available in NF-PitNETs. DRD2 effects on AKT are mediated by a β-arrestin 2-dependent mechanism in mouse striatum. The aim of this study was to investigate DRD2 effects on AKT phosphorylation and cell proliferation in human primary cultured NF-PitNET cells and in rat tumoral lactotroph cells MMQ, and to test β-arrestin 2 involvement. We found that DRD2 agonist BIM53097 induced a reduction of p- AKT /total-AKT ratio in MMQ (-32.8±17.6%, p<0.001 vs basal) and in a subset (n=15/41,36.6%) of NF-PitNETs (subgroup 1). In the remaining NF-PitNETs (subgroup 2), BIM53097 induced an increase of p- AKT. The ability of BIM53097 to reduce p-AKT correlated to its antimitotic effect, since the majority of subgroup 1 NF-PitNETs was responsive to BIM53097 and nearly all subgroup 2 NF-PitNETs were resistant. β-arrestin2 was expressed in MMQ and in 80% of subgroup 1 NF-PitNETs, whereas it was undetectable in 77% of subgroup 2 NF-PitNETs. In MMQ, β-arrestin 2 silencing prevented DRD2 inhibitory effects on p-AKT and cell proliferation. Accordingly, β-arrestin 2 transfection in subgroup 2 NF-PitNETs conferred to BIM53097 the ability to inhibit both p-AKT and cell growth. In conclusion, we demonstrated that β-arrestin 2 is required for DRD2 inhibitory effects on AKT phosphorylation and cell proliferation in MMQ and NF-PitNETs, paving the way for a potential role of β-arrestin 2 as a biomarker predicting NF-PitNETs responsiveness to treatment with dopamine agonists.

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[beta]-arrestin 2 expression is required for dopamine receptor type 2 (DRD2) inhibitory effects on Akt phosphorylation and cell proliferation in PRL-secreting and non functioning pituitary tumors

Endocrine Abstracts ◽

10.1530/endoabs.63.p264 ◽

2019 ◽

Author(s):

Federica Mangili ◽

Elena Giardino ◽

Donatella Treppiedi ◽

Rosa Catalano ◽

Marco Locatelli ◽

...

Keyword(s):

Cell Proliferation ◽

Dopamine Receptor ◽

Pituitary Tumors ◽

Receptor Type ◽

Inhibitory Effects ◽

Akt Phosphorylation

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Transdermal delivery of a somatostatin receptor type 2 antagonist using microneedle patch technology for hypoglycemia prevention

Drug Delivery and Translational Research ◽

10.1007/s13346-021-00944-3 ◽

2021 ◽

Author(s):

Amin GhavamiNejad ◽

Brian Lu ◽

Melisa Samarikhalaj ◽

Jackie Fule Liu ◽

Sako Mirzaie ◽

...

Keyword(s):

Transdermal Delivery ◽

Somatostatin Receptor ◽

Receptor Type ◽

Microneedle Patch

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Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2

Endocrine Related Cancer ◽

10.1677/erc.1.01191 ◽

2006 ◽

Vol 13 (3) ◽

pp. 955-962 ◽

Cited By ~ 67

Author(s):

E Ferrante ◽

C Pellegrini ◽

S Bondioni ◽

E Peverelli ◽

M Locatelli ◽

...

Keyword(s):

Tumor Cells ◽

Cultured Cells ◽

Somatostatin Receptor ◽

Hormone Secretion ◽

Somatostatin Analogs ◽

Receptor Type ◽

Apoptotic Activity ◽

Long Acting ◽

Induced Apoptosis

Somatostatin analogs currently used in the treatment of acromegaly and other neuroendocrine tumors inhibit hormone secretion and cell proliferation by binding to somatostatin receptor type (SST) 2 and 5. The antiproliferative pathways coupled to these receptors have been only partially characterized. The aim of this study was to evaluate the effect of octreotide and super selective SST2 (BIM23120) and SST5 (BIM23206) analogs on apoptotic activity and apoptotic gene expression in human somatotroph tumor cells. Eight somatotroph tumors expressing similar levels of SST2 and SST5 evaluated by real-time PCR and western blot analyses were included in the study. In cultured cells obtained from these tumors, octreotide induced a dose-dependent increase of caspase-3 activity (160 ± 20% vs basal at 10 nM) and cleaved cytokeratin 18 levels (172 ± 25% vs basal) at concentrations higher than 0.1 nM. This effect was due to SST2 activation since BIM23120 elicited comparable responses, while BIM23206 was ineffective. BIM23120-stimulated apoptosis was dependent on phosphatases, since it was abrogated by the inhibitor orthovanadate, and independent from the induction of apoptosis-related genes, such as p53, p63, p73, Bcl-2, Bax, BID, BIK, TNFSF8, and FADD. In somatotroph tumors, both BIM23120 and BIM2306 caused growth arrest as indicated by the increase in p27 and decrease in cyclin D1 expression. In conclusion, the present study showed that octreotide-induced apoptosis in human somatotroph tumor cells by activating SST2. This effect, together with the cytostatic action exerted by both SST2 and SST5 analogs, might account for the tumor shrinkage observed in acromegalic patients treated with long-acting somatostatin analogs.

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