Los receptores beta adrenérgicos inhiben la proliferación y estimulan la adhesión celular vía dos mecanismos distintos de señalización en células de mama humana MCF-10A

BRUZZONE A; LUTHY IA; PARIS H

Buenos Aires

Jornada; X Jornadas Cientificas de la Sociedad Argentina de Biología; 2008

Sociedad Argentina de Biología

Beta-adrenergic stimulation is linked to enhanced cyclic AMP (cAMP), which activates protein kinase A (PKA). However, another pathway involving the exchange pro­tein di­rec­tly activated by cAMP (Epac) has been described. Treatment of different human breast cancer cells with beta-adrenergic agonists is associated with diminished cell proli­fe­ra­tion. The objective of the present work was to study the effect of a beta-agonist on the proliferation and adhesion of non-tumoral human breast cells, MCF-10A, and to investigate the signalling pathways involved in these actions. MCF-10A cells incubated for 48 hs in the presence of 0.2 µM isoproterenol (ISO) exhibited a significant diminution of cell proliferation with respect to control (37 ± 3 %, p<0.001), associated with attenuated phos­pho­ry­la­tion of Erk 1/2. This latter effect was blocked by the PKA inhi­bi­tor H-89 and mimicked by forskolin, 8-Br-cAMP and 6-Bnz-cAMP (BNZ) but not by the Epac stimulator 8-CPT-2´-O-Me-cAMP (CTP), indicating involvement of PKA. The exposure of MCF-10A cells to 0.2 µM ISO for 4 hs caused a significant enhancement of cell adhesion (74 ± 2 % vs 1.2 ± 0.1 % of adherent cells after trypsin-EDTA treatment under mechanical agitation, p<0.0001). ISO-induced cell adhesion was not affected by H-89. On the other hand cells treated with CTP, but not BNZ, exhibited enhanced adhesion. As assessed by immuno-cytology with specific antibodies the effect of ISO was related with a redistribution of beta1-integrin and with reinforced cell-cell contacts. As a conclusion, beta-adrenergic stimulation of MCF-10A cells causes di­mi­nished proliferation via the PKA-Erk 1/2 pathway and enhanced cell adhesion via Epac signalling.