Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours.
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.
Hubina
Erika
E
Department of Endocrinology, William Harvey Research Institute, Barts and the London Medical School, Queen Mary College, Charterhouse Square, London EC1M 6BQ, UK.
Nanzer
Alexandra M
AM
Hanson
Matthew R
MR
Ciccarelli
Enrica
E
Losa
Marco
M
Gaia
Daniela
D
Papotti
Mauro
M
Terreni
Maria Rosaria
MR
Khalaf
Sahira
S
Jordan
Suzanne
S
Czirják
Sándor
S
Hanzély
Zoltán
Z
Nagy
György M
GM
Góth
Miklós I
MI
Grossman
Ashley B
AB
Korbonits
Márta
M
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
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