title: Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours.
abstract: OBJECTIVE
  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.affiliation: Department of Endocrinology, William Harvey Research Institute, Barts and the London Medical School, Queen Mary College, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Erika
authors.initials: E
authors.lastname: Hubina
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Nanzer
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hanson
authors.forename: Enrica
authors.initials: E
authors.lastname: Ciccarelli
authors.forename: Marco
authors.initials: M
authors.lastname: Losa
authors.forename: Daniela
authors.initials: D
authors.lastname: Gaia
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Terreni
authors.forename: Sahira
authors.initials: S
authors.lastname: Khalaf
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jordan
authors.forename: Sándor
authors.initials: S
authors.lastname: Czirják
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Hanzély
authors.forename: György M
authors.initials: GM
authors.lastname: Nagy
authors.forename: Miklós I
authors.initials: MI
authors.lastname: Góth
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Grossman
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D015282:Octreotide / Q000494:pharmacology*; D010902:Pituitary Gland / Q000166:cytology; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015175:Prolactinoma / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D013936:Thymidine / Q000493:pharmacokinetics; D014316:Tritium; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014316:Tritium; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013004:Somatostatin; C517782:pasireotide; D048049:Extracellular Signal-Regulated MAP Kinases; D015282:Octreotide; D013936:Thymidine