INVOLVEMENT OF MEK/ERK1/2 AND PI3K/AKT PATHWAYS IN THE REFRACTORY BEHAVIOR OF GH3B6 PITUITARY TUMOR CELLS TO THE INHIBITORY EFFECT OF TGFb1

PETITI JP; SOSA LDV; SABATINO ME; VACA AM; GUTIERREZ S; DE PAUL AL; TORRES AI

ENDOCRINOLOGY

ENDOCRINE SOC

Año: 2015 vol. 156 p. 534 - 547

0013-7227

Pituitary tumor cells have a poor response to the growth inhibitory effect of TGFb1, possibly resulting from the crosstalk of TGF/Smads signal with other signaling pathways, an undescribed mechanism in these tumoral cells. To address this hypothesis, we investigated whether the MEK/ERK1/2 and PI3K/Akt pathways were able to regulate the antimitogenic effect of TGF1 on GH3B6 cells. TGFb1 treatment decreased the cell proliferation and induced an activation of Smad2/3, effects that were potentiated by MEK (PD98059) and PI3K (LY294002) inhibitors, thus indicating the existence of a crosstalk between TGF1/Smad with the MEK/ERK1/2 or PI3K/Akt pathways. In addition, through immunoprecipitation assays, a direct interaction was observed between Smad2/ 3-ERK1/2 and Smad2/3-Akt, which decreased when the GH3B6 cells were incubated with TGFb1 in the presence of MEK or PI3K inhibitors, thereby suggesting that the ERK1/2 and Akt activated states were involved. These Smad2/3-ERK1/2 and Smad2/3-Akt associations were also confirmed by confocal and transmission electron microscopy. These findings indicate that the TGFb1-antimitogenic effect in GH3B6 cells was attenuated by the MEK/ERK1/2 and PI3K/Akt pathways via modulating Smad2/3 phosphorylation. This molecular mechanism could explain in part the refractory behavior of pituitary tumor cells to the inhibitory effect of TGFb1.