Synergic effects of TGFb1 and Octreotide on pituitary tumor cell proliferation

PEREZ P.; TORRES A.; SOSA L.; DE PAUL, A.; PICECH F.; GUTIéRREZ S.; PETITI J.P.

Praga

Congreso; 12th International Congress of Cell Biology - Programme and abstract book; 2016

The precise response to environment signals is essential for the cell function, development and survival, therefore an alteration in the receptors responsible of transmitting those signals into cells is closely associated with tumor progression and resistance to treatments. Pituitary adenomas exhibit a low expression of inhibitory receptors, as those for somatostatin (SSTR) and TGF-â1 (TGF-âR), which has been associated with the resistance that these tumors display against conventional therapy. Our main objective was to elucidate a possible crosstalk between both inhibitory pathways in pituitary adenoma cells. GH3 rat pituitary tumor cells were treated for 24 hours with SSTR and TGF-âR agonists, octreotide (OCT, 10 and 100 nM) and TGF-â1 (4 mg/ml) respectively. SSTRs and TGF-âRs mRNA expression was analysed by PCR, hormone secretion (PRL) by RIA, cell proliferation by immunocytochemistry for Ki67, and cycle progression by flow cytometry. In addition, the influence of the agonists on cell ultra-structure and morphology was examined by transmission electron microscopy.The co-incubation of OCT with TGF-â1 induced an increase of SSTR and TGF-â1R mRNA expression and a decrease of the proliferation marker Ki67 and PRL secretion compared to treatments alone. Furthermore, OCT diminished the expression of cell cycle regulators Cdk4 and Cyclin D1, and incremented the percentage of cells in S and G2/M phase. Nevertheless, none of the treatments induced changes in cell morphology. To summarize, these results prove that the treatment of OCT in presence of TGF-â1 modifies SSTRs and TâRs expression leading to an inhibition in cell proliferation and hormone secretion, which suggests a possible interaction between both anti-mitogenic signals in GH3 cells. Moreover, OCT exerts an anti-proliferative effect by decreasing the expression of proteins that control the cell cycle and possibly inducing cell cycle arrest in proliferative phases. Such results highlight the importance of comprehending the connection among different anti-mitogenic signalling pathways and how they can be modulated to obtain a better cell response on the context of tumoral resistance to treatments.