COMBINATION OF ANTI-PROLIFERATIVE SIGNALLING ACTIVATION FOR THE TREATMENT OF PITUITARY TUMORS

PICECH F.; SOSA L.; MUKDSI J. H.; TORRES A. I.; PETITI J. P.

Ciudad del Cabo

Congreso; 18 International Congress of Endocrinology (ICE); 2018

Current therapies for pituitary adenomas focus on stimulating somatostatin receptors (SSTRs) that inhibit cell proliferation and hormone secretion. However, half of patients undergo resistant to the SST analogue Octreotide (OCT), with the search for alternative strategies that overcome such resistant deserving investigation. We here analysed the anti-proliferative TGFβ1 signalling in combination with SST activation as a way to effectively control cell proliferation and hormonal secretion. First, the expression of SSTRs (SSTR2 and SSTR5) and TbRs (TbRI, TbRII) were found to be downregulated in different types of human pituitary tumours (9 non-functioning, 6 GH-, and 2 ACTH-secreting samples), compared to normal pituitaries (n=7) by IHC and western blot, suggesting a (lack of) receptor-mediated hyporesponsiveness. Then, GH3 pituitary tumour cells were treated in vitro with OCT (10 and 100 nM), TGFb1 (4 mg/ml) or a combination of both stimuli for 24h. The co-incubation of OCT/TGFb1 increased mRNA expression of TbRI, SSTR2, and SSTR5 (by qPCR), being correlated to a decrease in cell proliferation (Ki67 quantification) and PRL secretion (by RIA) comparing to single treatments. Finally, the transient transfection to overexpress SSTR2 induced a significant decrease in GH3 proliferation, as measured by BrdU incorporation, with an additional reduction when these cell were stimulated with OCT/TGFb1 combination.These findings suggest a possible crosstalk between somatostatin analogues and TGFb1 modulating both cell proliferation and hormonal secretion in pituitary adenomas, with such interaction representing a promising approach in the context of tumour resistance.