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EXPERIMENTAL STUDY |
1 Department of Endocrinology, William Harvey Research Institute, Barts and the London Medical School, Queen Mary College, Charterhouse Square, London EC1M 6BQ, UK, 2 Division of Endocrinology, Department of Medicine, National Medical Centre, 1135 Budapest, Hungary, 3 Departments of Internal Medicine and4 Pathology, Ospedale Molinette, University of Turin, 10100 Turin, Italy,5 Pituitary Unit of the Department of Neurosurgery, University Vita-Salute, 20132 Milan, Italy,6 National Institute of Neurosurgery, 1143 Budapest, Hungary and7 Neuroendocrine Research Laboratory, Department of Human Morphology, Semmelweis University, 1095 Budapest, Hungary
(Correspondence should be addressed to M Korbonits; Email: m.korbonits{at}qmul.ac.uk)
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.
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