title: Humanin inhibits apoptosis in pituitary tumor cells through several signaling pathways including NF-κB activation.
abstract: Humanin (HN) and Rattin (HNr), its homologous in the rat, are peptides with cytoprotective action in several cell types such as neurons, lymphocytes and testicular germ cells. Previously, we have shown that HNr is expressed in pituitary cells and that HN inhibited the apoptotic effect of TNF-α in both normal and tumor pituitary cells. The aim of the present study was to identify signaling pathways that mediate the antiapoptotic effect of HN in anterior pituitary cells from ovariectomized rats and in GH3 cells, a somatolactotrope cell line. We assessed the role of STAT3, JNK, Akt and MAPKs as well as proteins of the Bcl-2 family, previously implicated in the antiapoptotic effect of HN. We also evaluated the participation of NF-κB in the antiapoptotic action of HN. STAT3 inhibition reversed the inhibitory effect of HN on TNF-α-induced apoptosis in normal and pituitary tumor cells, indicating that STAT3 signaling pathway mediates the antiapoptotic effect of HN on pituitary cells. Inhibition of NF-κB pathway did not affect action of HN on normal anterior pituitary cells but blocked the cytoprotective effect of HN on TNF-α-induced apoptosis of GH3 cells, suggesting that the NF-κB pathway is involved in HN action in tumor pituitary cells. HN also induced NF-κB-p65 nuclear translocation in these cells. In pituitary tumor cells, JNK and MEK inhibitors also impaired HN cytoprotective action. In addition, HN increased Bcl-2 expression and decreased Bax mitochondrial translocation. Since HN expression in GH3 cells is higher than in normal pituitary cells, we may suggest that through multiple pathways HN could be involved in pituitary tumorigenesis.
authors.affiliation: Facultad de Medicina, Departamento de Biología Celular e Histología, Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.|CONICET, Instituto de Investigaciones Biomédicas (INBIOMED), Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.
authors.forename: María Florencia
authors.initials: MF
authors.lastname: Gottardo
authors.affiliation: CONICET, Instituto de Investigaciones Biomédicas (INBIOMED), Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.
authors.forename: Mariela
authors.initials: M
authors.lastname: Moreno Ayala
authors.affiliation: Facultad de Medicina, Departamento de Biología Celular e Histología, Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.|CONICET, Instituto de Investigaciones Biomédicas (INBIOMED), Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.
authors.forename: Jimena
authors.initials: J
authors.lastname: Ferraris
authors.affiliation: Facultad de Medicina, Departamento de Biología Celular e Histología, Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.|CONICET, Instituto de Investigaciones Biomédicas (INBIOMED), Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.
authors.forename: Sandra
authors.initials: S
authors.lastname: Zárate
authors.affiliation: CONICET, Instituto de Investigaciones Biomédicas (INBIOMED), Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pisera
authors.affiliation: CONICET, Instituto de Investigaciones Biomédicas (INBIOMED), Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.
authors.forename: Marianela
authors.initials: M
authors.lastname: Candolfi
authors.affiliation: Facultad de Medicina, Departamento de Biología Celular e Histología, Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.|CONICET, Instituto de Investigaciones Biomédicas (INBIOMED), Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Jaita
authors.affiliation: Facultad de Medicina, Departamento de Biología Celular e Histología, Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina. adyseili@fmed.uba.ar.|CONICET, Instituto de Investigaciones Biomédicas (INBIOMED), Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina. adyseili@fmed.uba.ar.
authors.forename: Adriana
authors.initials: A
authors.lastname: Seilicovich
keywords: Apoptosis; Bcl-2 family proteins; Humanin; NF-κB; Pituitary; STAT3