Endocrine Abstracts (2006) 11 P520

Role of PKA regulatory subunit 2B protein on cortisol-secreting adrenocortical cells proliferation

A Lania1, G Mantovani1, S Bondioni1, E Peverelli1, S Ferrero2, L Vicentini3, S Bosari2, P Beck-Peccoz1 & A Spada1


1Institute of Endocrine Sciences, University of Milan, Fondazione Ospedale Maggiore IRCCS, Milan, Italy; 2Pathology Unit, Department of Medicine, Surgery and Dentistry, A.O. San Paolo and Fondazione Ospedale Maggiore IRCCS, Milan, Italy; 3Endocrine Surgery Unit, Fondazione Ospedale Maggiore IRCCS, Milan, Italy.


The two regulatory subunits (R1 and R2) of PKA are differentially expressed in several cancer cell lines and studies indicate distinct roles for these subunits in growth control. Recently, mutations of the regulatory subunit 1A of PKA gene have been identified in patients with Carney complex (CNC). The aim of this study was to evaluate the expression of the different PKA regulatory subunits (R1A, R2A, R2B) in adrenocortical tumors not associated with CNC, as well as the effects of subunit activation on cell proliferation. Immunohistochemistry demonstrated an absent expression of R2B in all 10 cortisol-secreting adrenal tumors studied, while both R1A and R2A were expressed at high levels. Conversely, in all the adrenal carcinomas studied all the 3 regulatory subunits were expressed at high levels. Sequencing analysis of the R1A and R2B genes revealed a wild type sequence in all tumors. The effect of R1/R2 ratio on proliferation was assessed in mouse adrenocortical Y-1 cells that showed a similar pattern of R subunits expression compared to human normal adrenocortical cells. The R2-selective cAMP analogue 8-Cl cAMP dose-dependently inhibited Y-1 cell proliferation on one hand and stimulated apoptosis on the other. The anti-proliferative effect of R2B was further confirmed by the observation that R2B silencing by siRNA technique was associated an increase on Y-1 cell proliferation. Conversely, the R1-selective cAMP analogue 8-HA-cAMP stimulated the proliferation of the same cells. Finally, no effect of cAMP analogue was observed in NCI-H295R, a human adrenal carcinoma cell line. In conclusion, although a high R1/R2 ratio promotes cell proliferation in adrenocortical cells, the loss of R2B seems to be associated with a benign phenotype

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