Lack of oestrogenic inhibition of the NF-kB pathway in pituitary tumour cells

EIJO G; GOTTARDO MF; JAITA G; MORENO AYALA MA; ZÁRATE S; CANDOLFI M; PISERA D; SEILICOVICH A

JOURNAL OF NEUROENDOCRINOLOGY.

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2015

0953-8194

Activation of nuclear factor NFkB promotes cell proliferation and inhibits apoptosis. We have previously shown that oestrogens sensitise normal anterior pituitary cells to the apoptotic effect of tumour necrosis factor TNFα by inhibiting NFκB nuclear translocation. In the present study, we examined whether oestrogens also modulate the NFkB signalling pathway and apoptosis in GH3 cells, a rat somatolactotroph tumour cell line. As determined by Western blotting, 17β-oestradiol (E2 ) (10(-9) m) increased the nuclear concentration of NFkB/p105, p65 and p50 in GH3 cells. However, E2 did not modify the expression of Bcl-xL, a NF-κB target gene. TNFα induced apoptosis of GH3 cells incubated in either the presence or absence of E2 . Inhibition of the NFkB pathway using BAY 11-7082 (BAY) (5 μm) decreased the viability of GH3 cells and increased the percentage of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive GH3 cells. BAY also increased TNFα-induced apoptosis of GH3 cells, an effect that was further increased by an inhibitor of the c-Jun N-terminal protein kinase pathway, SP600125 (10 μm). We also analysed the role of the NFkB signalling pathway on proliferation and apoptosis of GH3 tumours in vivo. The administration of BAY to nude mice bearing GH3 tumours increased the number of TUNEL-positive cells and decreased the number of proliferating GH3 cells. These findings suggest that GH3 cells lose their oestrogenic inhibitory action on the NF-κB pathway and that the pro-apoptotic effect of TNF-α on these tumour pituitary cells does not require sensitisation by oestrogens as occurs in normal pituitary cells. NFkB was required for the survival of GH3 cells, suggesting that pharmacological inhibition of the NFkB pathway could interfere with pituitary tumour progression.