Somatostatin and its analogues negatively regulate the growth of multiple epithelial cell types. This anti-proliferative effect occurs through multiple mechanisms, one of which is cell cycle arrest at the G0/G1 phase. p27, a cyclin-dependent kinase inhibitor, has a negative influence on cell cycle progression, and there are recent data suggesting that somatostatin increases p27 levels. We have previously shown that pituitary adenoma cells contain less p27 protein than normal pituitary 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. In a preliminary study in tissue samples from acromegalic patients treated with somatostatin analogues before surgery, we found a positive correlation between strong p27 staining and the length of octreotide treatment. We have therefore hypothesised that somatostatin analogues may upregulate p27 protein levels and possibly down-regulate MAPK, which is an important signalling pathway mediating cell proliferation. We used octreotide, a primarily SSTR2 and SSTR5 agonist, and SOM230, an agonist with activity on all SSTRs except SSTR4.
Five pituitary adenoma tissues were studied for changes in p27 and MAPK. Human pituitary adenoma cells were dispersed in vitro and were treated with octreotide at 10-9M concentration and SOM230 at 10-6M concentration for 72 hours for p27 and for 10 minutes for MAPK. The activation of p27 and MAPK pathways were studied using immunoblotting. Somatostatin receptor expression of the samples was studied with RT-PCR. We detected up-regulation of p27 protein levels in all five samples treated with both octreotide and SOM230 compared to cells treated with media alone. The data on MAPK are currently under analysis. Our results suggest that the anti-proliferative effect of somatostatin and its analogues (octreotide and SOM230) involves the up-regulation of p27.
Keywords: pituitary tumour, octreotide, somatostatin230, p27, MAPK, cell cycle
04 - 06 Apr 2005
British Endocrine Societies