MODULATION OF ANTI-MITOGENIC SIGNALING IN PITUITARY TUMOR CELLS AS NEW THERAPEUTIC STRATEGIES

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

Buenos Aires, Argentina

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

SAIC

Clinical treatments for pituitary tumors are focused on stimulating receptors that inhibit proliferation and hormone secretion, such as those for TGFβ1 and somatostatin (SST). However, almost 40% of the patients who receive treatment with SST analogue, Octreotide (OCT), do not respond as expected and the mechanisms underlying this resistance remains still unknown.Our objectives were to evaluate TGFβ1 and SST receptors expression and to elucidate a possible crosstalk between both pathways in pituitary adenoma cells. We determined the expression of TβRI, TβRII, SSTR2 and SSTR5 by IHC and WB in normal pituitaries (n=7) and in different types of human pituitary adenoma samples: non-functioning (n=9), GH (n=6) and ACTH-secreting tumors (n=2). GH3 rat pituitary tumor cells were treated for 24 h with OCT (10 and 100 nM) and/or TGFβ1 (4 mg/ml). SSTRs and TβRs mRNA was analysed by qPCR, hormone secretion (PRL) by RIA and cell proliferation by ICC for Ki67. Statistics: ANOVA-Fisher, T-Test.Human pituitary tumor samples exhibited a decreased in SSTRs and TβRs protein expression although variable between different types of adenomas compared to normal pituitaries. In addition, we demonstrated that the co-incubation of OCT with TGFβ1 induced an increase of SSTRs and TβRI mRNA expression, effect that was associated with a decrease of proliferation marker Ki67 and PRL secretion compared to treatments alone (p＜0,05). These findings suggest that pituitary tumor resistance to treatments could be explained, at least in part, by the decreased in anti-mitogenic receptors expression. Furthermore, the synergic effect of OCT and TGFβ1 on cell proliferation and hormone secretion indicate a possible interaction between both anti-mitogenic signals in GH3 cells. 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 tumor resistance to treatments.