Somatostatin and its analog lanreotide inhibit the proliferation of dispersed human non-functioning pituitary adenoma cells in vitro

Florio, Tullio; Thellung, Stefano; Arena, Sara; Corsaro, Alessandro; Spaziante, Renato; Gussoni, Gualberto; Acuto, Giancarlo; Giusti, Massimo; Giordano, Giulio; Schettini, Gennaro

doi:10.1530/eje.0.1410396

Cited by 75 publications

(51 citation statements)

References 53 publications

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“…In this adenoma, the high level of SSTR5 mRNA is also an unusual feature. The SSTR5 subtype has been found in only 10/35 of the nonfunctioning pituitary adenomas in previous studies (5,22). In our mixed tumour, its presence is not surprising, while SSTR5 has been found highly expressed in PRL-secreting adenomas (10,12).…”

Section: Discussionsupporting

confidence: 48%

“…If octreotide was poorly effective upon tumour shrinkage, a significant reduction in serum FSH concentrations could be found in two out of four patients under long-term octreotide administration (4). More recently, it was shown by cell culture studies that somatostatin and its analogue, lanreotide, inhibited the proliferation of dispersed human non-functioning pituitary cells (5), which, in their majority, do synthesize LH, FSH or the a subunit (6±8). Such data, even if limited, indicated a possible inhibitory effect of somatostatin or its analogues in some gonadotroph tumours.…”

Section: Introductionmentioning

confidence: 99%

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A luteinizing hormone-, alpha-subunit- and prolactin-secreting pituitary adenoma responsive to somatostatin analogs: in vivo and in vitro studies

Saveanu¹,

Morange-Ramos²,

Gunz³

et al. 2001

European Journal of Endocrinology

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Objective: Evaluation of the efficiency of somatostatin analogues in the treatment of a mixed luteinizing hormone (LH)-, a-subunit-, prolactin (PRL)-secreting pituitary adenoma. Design: A 30-year-old woman, with amenorrhaea-galactorrhaea, presented with a pituitary macroadenoma. The endocrine evaluation showed high plasma levels of PRL, LH, and a-subunit inhibited by 65%, 65% and 33% respectively under octreotide test (200 mg, s.c.). Long-term treatment with slow release (SR) lanreotide (30 mg/10 days, i.m.) restored menstrual cycles and normalized PRL values. Due to persisting supranormal levels of LH and a-subunit, and to the absence of tumoral shrinkage, the adenoma was resected by the transsphenoidal route. Methods: In vitro characterization of the somatostatin receptor subtypes (SSTR) expression and functionality. Real-time polymerase chain reaction was performed to quantify the expression of SSTR mRNAs and functionality of the SSTRs was assessed in cell culture studies with various concentrations of native somatostatin (SRIF-14) and of analogues preferential for SSTR2 or SSTR5.Results: This adenoma presented with high levels of SSTR2, SSTR3 and SSTR5 mRNAs, as compared with a series of gonadotroph adenomas. In cell culture studies, PRL, LH and a-subunit were inhibited by 60%, 47% and 33% respectively by SRIF-14 at a concentration of 10 nmol/l. The SSTR2 (BIM-23197, lanreotide) and SSTR5 (BIM-23268) preferential analogues both produced a partial 21±38% inhibition of PRL, LH, and a-subunit release. Discussion: In this plurihormonal-secreting adenoma, the high efficacy of somatostatin analogues to inhibit PRL, LH and a-subunit secretion in vivo may be explained by the unusually high level of expression and by the functionality of both SSTR2 and SSTR5 receptor subtypes.

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Section: Discussionsupporting

confidence: 48%

Section: Introductionmentioning

confidence: 99%

A luteinizing hormone-, alpha-subunit- and prolactin-secreting pituitary adenoma responsive to somatostatin analogs: in vivo and in vitro studies

Saveanu¹,

Morange-Ramos²,

Gunz³

et al. 2001

European Journal of Endocrinology

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“…Elk1 is a common target for the MAPK/ERK pathway (Turjanski et al 2007), and mammalian SSTR1 previously has been linked to increased Elk1 transcriptional activity through phosphorylation of the ERK pathway (Florio et al 1999). C/EBPb is the target of regulation by two signal cascades: the PI3K/Akt activation results in dephosphorylation of C/EBPb from one site, whereas ERK activation promotes phosphorylation at another site of C/EBPb (Schrem et al 2004, Cui et al 2008.…”

Section: Discussionmentioning

confidence: 99%

Rainbow trout somatostatin receptor subtypes SSTR1A, SSTR1B, and SSTR2 differentially activate the extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways in transfected cells

Hagemeister

Kittilson²,

Bergan³

et al. 2010

Journal of Molecular Endocrinology

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Previously, we reported that extracellular signal-regulated kinase (ERK) and protein kinase B (Akt), a downstream target of phosphatidylinositol 3-kinase (PI3K), mediated somatostatin (SS) inhibition of GH receptor, IGF1, and IGF1 receptor expression. In this study, we used Chinese hamster ovary-K1 cells that stably transfected individually with trout SS receptors (SSTR1A, SSTR1B, and SSTR2) to elucidate receptor-effector pathway linkages. SS induced ERK and Akt activation in a time-and concentration-related manner in all SSTR-expressing cells; however, the PI3K/Akt pathway was activated to a greater extent through SSTR1A than through either SSTR1B or SSTR2, whereas the ERK pathway was activated to a greater extent though SSTR2 than through either SSTR1A or SSTR1B. Although the ERK pathway inhibitor U0126 had no effect on Akt activation, the PI3K inhibitor LY294002 reduced ERK activation to near control levels in all SSTR-expressing cell lines, suggesting some cross talk between the pathways, possibly at the level of c-Raf, the phosphorylation of which also was induced by SS via each SSTR. Pertussis toxin (PTX) completely abolished SS-induced activation of ERK and Akt in SSTR1A-, SSTR1B-, and SSTR2-expressing cells, suggesting that these receptors link to the ERK and PI3K/Akt pathways via PTX-sensitive G-proteins. SS-induced activation of Elk1, Stat3, and C/EBPb also was mediated by each of the trout SSTRs. These findings establish important receptor-effector pathway linkages for fish SSTRs and provide insight into the molecular mechanisms by which SSs may elicit diverse physiological effects in target cells.

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“…In vitro treatment of human NFPAs with octreotide or lanreotide inhibits cell proliferation (23,24) and octreotide has been shown to induce G0/G1 cell-cycle arrest and thus prevent DNA synthesis in rat GH3 cells (25), but changes in the p27 and the MAP kinase pathways in response to SST analogues have not been previously investigated in pituitary adenomas, despite the fact that pituitary adenomas are one of the primary treatment targets of SST analogues. We have shown previously that normal somatotroph cells contain more p27 protein than somatotroph adenoma cells: for example, 75% of somatotroph cells in the normal pituitary show positive immunostaining for p27, while somatotroph cells in adenomas show only 40% p27 staining (26).…”

Section: Discussionmentioning

confidence: 99%

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

et al. 2006

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Objectives: Somatostatin (SST) analogues play an important role in the medical management of somatotroph pituitary adenomas and new agonists have the potential to be effective in a wider group of pituitary and other tumours. The anti-proliferative effect of SST occurs through multiple mechanisms, one of which is cell-cycle arrest, where p27, a cyclin-dependent kinase inhibitor, is an important regulator. We hypothesised that SST may upregulate p27 protein levels and downregulate the MAP kinase pathway in these tumours. Methods: Human pituitary adenoma cells and rat pituitary cell line (GH3) were cultured and treated in vitro with octreotide and the broad-spectrum SST agonist SOM230 (pasireotide). Immunoblotting for p27 and phospho-ERK (pERK) was performed and proliferation assessed by [3 H]-thymidine incorporation. Histological samples from acromegalic patients treated with octreotide before surgery were immunostained for p27 and compared to samples from untreated patients matched for sex, age, tumour size, extension and invasiveness. Results: We detected upregulation of p27 protein levels with SST analogue treatment in vitro in human pituitary adenoma samples. pERK1/2 was inhibited by SST analogues in both the human samples and GH3 cells. SST and its analogues inhibited the proliferation of GH3 cells. p27 immunostaining was stronger in samples from patients with longer preoperative octreotide treatment (more than 6 months) than in samples from patients with shorter treatment periods. Conclusions: This study demonstrates that SST-mediated growth inhibition is associated with the downregulation of pERK and upregulation of p27. More potent and broader-spectrum SST analogues are likely to play an increasing role in the treatment of tumours, where the MAP kinase pathway is overactivated.

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Somatostatin and its analog lanreotide inhibit the proliferation of dispersed human non-functioning pituitary adenoma cells in vitro

Cited by 75 publications

References 53 publications

A luteinizing hormone-, alpha-subunit- and prolactin-secreting pituitary adenoma responsive to somatostatin analogs: in vivo and in vitro studies

A luteinizing hormone-, alpha-subunit- and prolactin-secreting pituitary adenoma responsive to somatostatin analogs: in vivo and in vitro studies

Rainbow trout somatostatin receptor subtypes SSTR1A, SSTR1B, and SSTR2 differentially activate the extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways in transfected cells

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

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