Combination of anti-proliferative signalling activation for the treatment of pituitary tumors

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

Cape Town

Congreso; 18th International congress of endocrinology; 2018

Current therapies for pituitary adenomas focus on stimulatingsomatostatin receptors (SSTRs) that inhibit cell proliferation andhormone secretion. However, half of patients undergo resistant tothe SST analogue Octreotide (OCT), with the search for alternativestrategies that overcome such resistant deserving investigation. Wehere analysed the anti-proliferative TGFβ1 signalling in combinationwith SST activation as a way to effectively control cell proliferation andhormonal secretion. First, the expression of SSTRs (SSTR2 and SSTR5)and TβRs (TβRI, TβRII) were found to be downregulated in differenttypes of human pituitary tumours (9 non-functioning, 6 GH-, and2 ACTH-secreting samples), compared to normal pituitaries (n=7)by IHC and western blot, suggesting a (lack of ) receptor-mediatedhyporesponsiveness. Then, GH3 pituitary tumour cells were treated invitro with OCT (10 and 100 nM), TGFβ1 (4 mg/ml) or a combination ofboth stimuli for 24h. The co-incubation of OCT/TGFβ1 increased mRNAexpression of TβRI, SSTR2, and SSTR5 (by qPCR), being correlated to adecrease in cell proliferation (Ki67 quantification) and PRL secretion (byRIA) comparing to single treatments. Finally, the transient transfection tooverexpress SSTR2 induced a significant decrease in GH3 proliferation,as measured by BrdU incorporation, with an additional reduction whenthese cell were stimulated with OCT/TGFβ1 combination.These findings suggest a possible crosstalk between somatostatinanalogues and TGFβ1 modulating both cell proliferation and hormonalsecretion in pituitary adenomas, with such interaction representing apromising approach in the context of tumour resistance.