title: Lack of Oestrogenic Inhibition of the Nuclear Factor-κB Pathway in Somatolactotroph Tumour Cells.
abstract: Activation of nuclear factor (NF)-κB 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 (TNF)-α by inhibiting NF-κB nuclear translocation. In the present study, we examined whether oestrogens also modulate the NF-κB 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 NF-κB/p105, p65 and p50 in GH3 cells. However, E2 did not modify the expression of Bcl-xL, a NF-κB target gene. TNF-α induced apoptosis of GH3 cells incubated in either the presence or absence of E2 . Inhibition of the NF-kB 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 TNF-α-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 NF-κB 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. NF-κB was required for the survival of GH3 cells, suggesting that pharmacological inhibition of the NF-κB pathway could interfere with pituitary tumour progression.
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
authors.forename: G
authors.initials: G
authors.lastname: Eijo
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
authors.forename: M F
authors.initials: MF
authors.lastname: Gottardo
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
authors.forename: G
authors.initials: G
authors.lastname: Jaita
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
authors.forename: M L
authors.initials: ML
authors.lastname: Magri
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Moreno Ayala
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
authors.forename: S
authors.initials: S
authors.lastname: Zárate
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Candolfi
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
authors.forename: D
authors.initials: D
authors.lastname: Pisera
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
authors.forename: A
authors.initials: A
authors.lastname: Seilicovich
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D052682:Lactotrophs / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D004967:Estrogens; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha
keywords: NF-κB; TNF-α; apoptosis; oestrogens; pituitary