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

Abstract

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 [3H]-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.

• Authors: Erika Hubina, Alexandra M Nanzer, Matthew R Hanson, Enrica Ciccarelli, Marco Losa, Daniela Gaia, Mauro Papotti, Maria Rosaria Terreni, Sahira Khalaf, Suzanne Jordan, Sándor Czirják, Zoltán Hanzély, György M Nagy, Miklós I Góth, Ashley B Grossman, Márta Korbonits
• Journal: European journal of endocrinology (Eur J Endocrinol) Vol. 155 Issue 2 Pg. 371-9 (Aug 2006) ISSN: 0804-4643 [Print] England
• PMID: 16868153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Tritium
• Cyclin-Dependent Kinase Inhibitor p27
• Somatostatin
• pasireotide
• Extracellular Signal-Regulated MAP Kinases
• Octreotide
• Thymidine

Topics

• Adenoma (drug therapy, metabolism)
• Animals
• Antineoplastic Agents, Hormonal (pharmacology)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Down-Regulation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Growth Hormone-Secreting Pituitary Adenoma (drug therapy, metabolism)
• Humans
• In Vitro Techniques
• MAP Kinase Signaling System (drug effects)
• Octreotide (pharmacology)
• Pituitary Gland (cytology)
• Pituitary Neoplasms (drug therapy, metabolism)
• Prolactinoma (drug therapy, metabolism)
• Rats
• Somatostatin (analogs & derivatives, pharmacology)
• Thymidine (pharmacokinetics)
• Tritium
• Up-Regulation (drug effects)