cAMP exerts proliferative and anti-proliferative effects in pituitary cells of different types by activating both cAMP-dependent protein kinase A and exchange proteins directly activated by cAMP

Eleonora Vitali; Erika Peverelli; Giovanna Mantovani; Elena Giardino; Andrea G. Lania; Paolo Beck-Peccoz; Anna Spada

doi:10.1530/endoabs.32.P827

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Endocrine Abstracts (2013) 32 P827 | DOI: 10.1530/endoabs.32.P827

ECE2013 Poster Presentations Pituitary–Basic (<emphasis role="italic">Generously supported by IPSEN</emphasis>) (17 abstracts)

cAMP exerts proliferative and anti-proliferative effects in pituitary cells of different types by activating both cAMP-dependent protein kinase A and exchange proteins directly activated by cAMP

Eleonora Vitali ¹ , Erika Peverelli ¹ , Giovanna Mantovani ¹ , Elena Giardino ¹ , Andrea G. Lania ² , Paolo Beck-Peccoz ¹ & Anna Spada ¹

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¹Endocrine Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; ²Endocrine Unit, IRCCS Humanitas Clinical Institute, Rozzano, Italy.

cAMP is implicated in the inhibition or stimulation of proliferation depending on cell type. The activation of cAMP–PKA pathway generates proliferative signals in GH-secreting adenomas whereas this effect is not present, or even opposite, in non-functioning pituitary cells (NFPA). Although cAMP effects were initially attributed to PKA activation, recently the discovery of two cAMP-activated guanine nucleotide exchange factors (Epac1,2) was proposed as a novel mechanism for governing signalling specificity within the cAMP cascade. The aim of the present study was to investigate the effects of cAMP in different pituitary cell types on cell proliferation and to determine the specific role of PKA and Epac in mediating these effects.

We tested the effects of different cAMP analogs (PKA-selective, Epac-selective or non selective) on cell proliferation, evaluating also the expression of cyclin D1/D3 and the cyclin dependent kinase inhibitor p27, in different pituitary adenomas (GH-, PRL-secreting or non secreting adenomas) and in appropriate cell lines (GH3, MMQ and HP75).

We found that non selective cAMP analog caused a 50% stimulation of somatotroph cells proliferation, whereas they exerted an opposite inhibitory effect on lactotrophs (−55%) and non-functioning (−58%) pituitary cells, these data being obtained also in the corresponding cell lines and confirmed by the expression of CD1, CD3, p27 proteins. Moreover, stimulatory and inhibitory effects induced by cAMP analog were mimicked by the PKA- and Epac-selective cAMP analogs.

In conclusion, we demonstrated that cAMP exerted opposite effects on proliferation in different pituitary cell types and that these effects are mediated by both PKA and Epac through the activation of different pathways, i.e. CREB and Rap1 respectively.