scholarly journals AIP and the somatostatin system in pituitary tumours

2017 ◽  
Vol 235 (3) ◽  
pp. R101-R116 ◽  
Author(s):  
Alejandro Ibáñez-Costa ◽  
Márta Korbonits
Keyword(s):  
Zinc Finger Protein ◽  
Tumour Size ◽  
Somatostatin Receptor ◽  
Hormone Secretion ◽  
Somatostatin Analogues ◽  
Pharmacological Therapy ◽  
Interacting Protein ◽  
Aryl Hydrocarbon

Classic somatostatin analogues aimed at somatostatin receptor type 2, such as octreotide and lanreotide, represent the mainstay of medical treatment for acromegaly. These agents have the potential to decrease hormone secretion and reduce tumour size. Patients with a germline mutation in the aryl hydrocarbon receptor-interacting protein gene, AIP, develop young-onset acromegaly, poorly responsive to pharmacological therapy. In this review, we summarise the most recent studies on AIP-related pituitary adenomas, paying special attention to the causes of somatostatin resistance; the somatostatin receptor profile including type 2, type 5 and truncated variants; the role of G proteins in this pathology; the use of first and second generation somatostatin analogues; and the role of ZAC1, a zinc-finger protein with expression linked to AIP in somatotrophinoma models and acting as a key mediator of octreotide response.

scholarly journals Resistance to octreotide LAR in acromegalic patients with high SSTR2 expression: analysis of AIP expression

2012 ◽  
Vol 56 (8) ◽  
pp. 501-506 ◽  
Author(s):  
Leandro Kasuki ◽  
Leandro M. Colli ◽  
Paula C. L. Elias ◽  
Margaret de Castro ◽  
Mônica R. Gadelha
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Molecular Data ◽  
Curative Surgery ◽  
Interacting Protein ◽  
Octreotide Lar ◽  
Expression Levels ◽  
Aryl Hydrocarbon

We present here the clinical and molecular data of two patients with acromegaly treated with octreotide LAR after non-curative surgery, and who presented different responses to therapy. Somatostatin receptor type 2 and 5 (SSTR2 and SSTR5), and aryl hydrocarbon receptor-interacting protein (AIP) expression levels were analyzed by qPCR. In both cases, high SSTR2 and low SSTR5 expression levels were detected; however, only one of the patients achieved disease control after octreotide LAR therapy. When we analyzed AIP expression levels of both cases, the patient whose disease was controlled after therapy exhibited AIP expression levels that were two times higher than the patient whose disease was still active. These two cases illustrate that, although the currently available somatostatin analogs bind preferentially to SSTR2, some patients are not responsive to therapy despite high expression of this receptor. This difference could be explained by differences in post-receptor signaling pathways, including the recently described involvement of AIP. Arq Bras Endocrinol Metab. 2012;56(8):501-6

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

2006 ◽  
Vol 13 (3) ◽  
pp. 955-962 ◽  
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.

scholarly journals AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients

2019 ◽  
Vol 8 (4) ◽  
pp. 367-377 ◽  
Author(s):  
Adrian F Daly ◽  
Liliya Rostomyan ◽  
Daniela Betea ◽  
Jean-François Bonneville ◽  
Chiara Villa ◽  
...  
Keyword(s):  
First Generation ◽  
Follicular Thyroid Carcinoma ◽  
Somatostatin Analogs ◽  
Hormonal Control ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Tumor Residue ◽  
Baseline Levels

Acromegaly is a rare disease due to chronic excess growth hormone (GH) and IGF-1. Aryl hydrocarbon receptor interacting protein (AIP) mutations are associated with an aggressive, inheritable form of acromegaly that responds poorly to SST2-specific somatostatin analogs (SSA). The role of pasireotide, an SSA with affinity for multiple SSTs, in patients with AIP mutations has not been reported. We studied two AIP mutation positive acromegaly patients with early-onset, invasive macroadenomas and inoperable residues after neurosurgery. Patient 1 came from a FIPA kindred and had uncontrolled GH/IGF-1 throughout 10 years of octreotide/lanreotide treatment. When switched to pasireotide LAR, he rapidly experienced hormonal control which was associated with marked regression of his tumor residue. Pasireotide LAR was stopped after >10 years due to low IGF-1 and he maintained hormonal control without tumor regrowth for >18 months off pasireotide LAR. Patient 2 had a pituitary adenoma diagnosed when aged 17 that was not cured by surgery. Chronic pasireotide LAR therapy produced hormonal control and marked tumor shrinkage but control was lost when switched to octreotide. Tumor immunohistochemistry showed absent AIP and SST2 staining and positive SST5. Her AIP mutation positive sister developed a 2.5 cm follicular thyroid carcinoma aged 21 with tumoral loss of heterozygosity at the AIP locus and absent AIP staining. Patients 1 and 2 required multi-modal therapy to control diabetes. On stopping pasireotide LAR after >10 years of treatment, Patient 1’s glucose metabolism returned to baseline levels. Long-term pasireotide LAR therapy can be beneficial in some AIP mutation positive acromegaly patients that are resistant to first-generation SSA.

scholarly journals Pegvisomant in combination with long-acting somatostatin analogues in acromegaly: the role of the GH receptor deletion of exon 3

2015 ◽  
Vol 173 (5) ◽  
pp. 553-561 ◽  
Author(s):  
S E Franck ◽  
A J van der Lely ◽  
P J D Delhanty ◽  
J O L Jørgensen ◽  
S J C M M Neggers
Keyword(s):  
Somatostatin Receptor ◽  
Serum Levels ◽  
Somatostatin Analogues ◽  
High Dose ◽  
Gh Receptor ◽  
Hardy Weinberg Equilibrium ◽  
Baseline Characteristics ◽  
Long Acting ◽  
Somatostatin Receptor Ligand

BackgroundDoses of the GH receptor (GHR) antagonist pegvisomant (PEGV) that normalize insulin-like growth factor 1 (IGF1) levels vary widely among acromegaly patients. Predictors for PEGV response are baseline IGF1 levels, sex, body weight and previous radiotherapy. A GHR polymorphism lacking exon 3 (d3-GHR) is frequent in the general population. The influence of d3-GHR on PEGV responsiveness in acromegaly is unclear.ObjectiveTo assess the influence of d3-GHR on IGF1 levels and PEGV responsiveness in acromegaly patients using combined PEGV and long-acting somatostatin receptor ligand (LA-SRIF) treatment.DesignData were collected at the Rotterdam Pituitary Centre between 2004 and 2013. Patients with elevated IGF1 levels (>1.2 upper limit of normal; n=112) and over 6 months of high-dose LA-SRIF treatment were co-treated with PEGV. GHR genotype was assessed using genomic DNA in 104 patients.ResultsD3-GHR was observed in 51 (49.0%) of the patients (7.7% homozygous, 41.3% heterozygous) and was in Hardy–Weinberg equilibrium (P=0.859). Baseline characteristics were similar in d3-GHR and full-length (fl)-GHR genotypes. During PEGV/LA-SRIF treatment IGF1 levels were not different between d3-carriers and non-carriers. Similarly, no difference in PEGV dose required to normalize IGF1 (P=0.337) or PEGV serum levels (P=0.433) was observed between the two groups. However, adenoma size decreased significantly (>20% of largest diameter) in 25.6% of the fl-GHR genotype but only in 7.5% of d3-carriers (P=0.034, OR: 4.6 (CI: 1.1–18.9)).ConclusionsGHR genotype does not predict the IGF1 normalizing dose of PEGV in acromegaly patients using combination PEGV/LA-SRIF treatment. However, fewer d3-carriers showed significant reductions in adenoma size.

scholarly journals Augmented Growth Hormone Secretion and Stat3 Phosphorylation in an Aryl Hydrocarbon Receptor Interacting Protein (AIP)-Disrupted Somatotroph Cell Line

PLoS ONE ◽  
2016 ◽  
Vol 11 (10) ◽  
pp. e0164131 ◽  
Author(s):  
Takashi Fukuda ◽  
Tomoko Tanaka ◽  
Yuriko Hamaguchi ◽  
Takako Kawanami ◽  
Takashi Nomiyama ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Aryl Hydrocarbon Receptor ◽  
Cell Line ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Stat3 Phosphorylation

The role of microRNA miR-34a in the regulation of aryl hydrocarbon receptor interacting protein

2013 ◽  
pp. 1-1
Author(s):  
Judit Denes ◽  
Leandro Kasuki ◽  
Giampaolo Trivellin ◽  
Monica Gadelha ◽  
Marta Korbonits
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Interacting Protein ◽  
Aryl Hydrocarbon

Somatostatin receptor type 2 trafficking through the cytoskeleton: role of scaffolding proteins Filamin A and [beta]-arrestin 2

2019 ◽  
Author(s):  
Donatella Treppiedi ◽  
Elena Giardino ◽  
Rosa Catalano ◽  
Federica Mangili ◽  
Marco Locatelli ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Receptor Type ◽  
Scaffolding Proteins ◽  
Filamin A

Role of AIP and its homologue the blindness-associated protein AIPL1 in regulating client protein nuclear translocation

2004 ◽  
Vol 32 (4) ◽  
pp. 643-645 ◽  
Author(s):  
J. van der Spuy ◽  
M.E. Cheetham
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Nuclear Translocation ◽  
Protein Translocation ◽  
Potential Functions ◽  
Client Protein ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Leber’S Congenital Amaurosis

Mutations in the AIPL1 (aryl hydrocarbon receptor interacting protein-like 1) cause the blinding disease Leber's congenital amaurosis. AIPL1 is a homologue of the AIP. AIP functions as part of a chaperone heterocomplex to facilitate signalling by the AhR and plays an important role in regulating the nuclear translocation of the receptor. We review the evidence for the role of AIP in protein translocation and compare the potential functions of AIPL1 in the translocation of its interacting partner the NEDD8 ultimate buster protein 1.

scholarly journals Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations

2013 ◽  
Vol 20 (5) ◽  
pp. 753-766 ◽  
Author(s):  
Marie-Lise Jaffrain-Rea ◽  
Sandra Rotondi ◽  
Annarita Turchi ◽  
Gianluca Occhi ◽  
Anne Barlier ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Aryl Hydrocarbon Receptor ◽  
Primary Cultures ◽  
Gene Mutations ◽  
Somatostatin Analogues ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Tumour Shrinkage ◽  
Suprasellar Extension

Germline aryl hydrocarbon receptor interacting protein (AIP) gene mutations confer a predisposition to pituitary adenoma (PA), predominantly GH-secreting (GH-PA). As recent data suggest a role for AIP in the pathogenesis of sporadic GH-PA and their response to somatostatin analogues (SSA), the expression of AIP and its partner, aryl hydrocarbon receptor (AHR), was determined by semiquantitative immunohistochemistry scoring in 62 sporadic GH-PA (37 treated with SSA preoperatively). The influence ofGspstatus was studied in a subset of tumours (n=39, 14Gsp+) and six GH-PA were available for primary cultures. AIP and AHR were detected in most cases, with a positive correlation between AIP and cytoplasmic AHR (P=0.012). Low AIP expression was significantly more frequent in untreated vs SSA-treated tumours (44.0 vs 20.5%,P=0.016). AHR expression or localisation did not differ between the two groups. Similarly,in vitrooctreotide induced a median twofold increase in AIP expression (range 1.2–13.9,P=0.027) in GH-PA. In SSA-treated tumours, the AIP score was significantly higher in the presence of preoperative IGF1 decrease or tumour shrinkage (P=0.008 andP=0.014 respectively). In untreated tumours, low AIP expression was significantly associated with invasiveness (P=0.028) and suprasellar extension (P=0.019). The only effect ofGspstatus was a significantly lower nuclear AHR score inGsp+vsGsp−tumours (P=0.025), irrespective of SSA. In conclusion, AIP is involved in the aggressiveness of sporadic GH-PA, regardless ofGspstatus, and AIP up-regulation in SSA-treated tumours is associated with a better preoperative response, with no clear role for AHR.

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