INBIOMED   24026
INSTITUTO DE INVESTIGACIONES BIOMEDICAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Deciphering the signalling pathways mediating the non-classical antiproliferative and proapoptotic effects of Prolactin in lactotrope cells
Autor/es:
FERRARIS JIMENA; IRIZARRI, MARTIN; PISERA, DANIEL; ORRILLO, SANTIAGO; GOFFIN, VINCENT; DE DIOS, NATALY; SEILICOVICH ADRIANA
Lugar:
COLORADO
Reunión:
Congreso; FASEB-GROWTH HORMONE/PROALCTIN FAMILY IN BIOLOGY AND DISEASE; 2017
Institución organizadora:
FASEB
Resumen:
Prolactinomas are the most commonintracranial tumours. Although dopamine agonist treatment is efficient in >90%of prolactinoma patients, there is currently no pharmacological treatment fordopamine-resistant cases. Some oncogenes (like RAS or PTTG) have been proposedto contribute to prolactinoma ehiology, but evidence is lacking to support thatthe mutation of a single gene may be responsible for prolactinoma occurrence. Inaddition, sporadic prolactinomas are much more frequent than familial cases. Hence,the disease is increasingly viewed as a ?problem of signal transduction?. Inthis context, the identification of factors and signalling pathways thatcontrol lactotrope cell turnover/homeostasis is needed in order to nourish newtherapeutic developments. We have previouslyshown that prolactin (PRL)acts as a proapoptotic and antiproliferative factor on lactotropes, which iscritical to maintain anterior pituitary cell homeostasis (Ferraris et al, 2012,2013, 2014). These effects contrast with the classical antiapoptotic and/orproliferative actions exerted by PRL in most of its other target tissues (e.g.mammary gland, prostate, lymphoid cells). The aim of this study was toinvestigate the PRLR-triggered signalling pathways mediating thesenon-classical effects in the pituitary.  Wefirst incubated GH3 mammosomatotrope cells with the pure PRLR antagonist∆1?9-G129R-hPRL in order to inhibit signalling cascades activated by theautocrine/paracrine PRL loop. Then the consequences on i) the phosphorylationstatus of canonical PRLR effectors including STAT5, STAT3, ERK1/2, P38 MAPK andAkt, and ii) the expression of Bax and Bcl-2 were determined using western blotand immunofluorescence. In other experiments, cells were incubated with ∆1?9-G129R-hPRL,alone or in combination with validated pharmacological inhibitors of several PRLReffectors (Jak2, STAT5, STAT3, MEK/ERK1/2, P38 MAPK and PI3K/Akt), then theeffects on cell apoptosis (TUNEL assay) and proliferation (BrdU incorporation)were measured. Together, our results suggest that i) Jak2/STAT5 pathway isconstitutively active in GH3 cells and contributes to PRL-induced apoptosis byincreasing Bax/Bcl-2 ratio, ii) STAT3 mediates the antiproliferative effects ofPRL, iii) PRL inhibits ERK1/2 and Akt phosphorylation thereby contributing to theproapoptotic effect, and iv) PI3K/Akt and p38 MAPK pathways participate in PRL-mediatedcontrol of lactotrope proliferation. Based on these results, we hypothesizethat the alteration of PRL-mediated control of lactotrope homeostasis due to thedysregulation of any of the mechanisms of actions described above maycontribute to the pathogenesis of prolactinomas.