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Title: Different expression of protein kinase A (PKA) regulatory subunits in cortisol-secreting adrenocortical tumors: Relationship with cell proliferation

The four regulatory subunits (R1A, R1B, R2A, R2B) of protein kinase A (PKA) are differentially expressed in several cancer cell lines and exert distinct roles in growth control. Mutations of the R1A gene have been found in patients with Carney complex and in a minority of sporadic primary pigmented nodular adrenocortical disease (PPNAD). The aim of this study was to evaluate the expression of PKA regulatory subunits in non-PPNAD adrenocortical tumors causing ACTH-independent Cushing's syndrome and to test the impact of differential expression of these subunits on cell growth. Immunohistochemistry demonstrated a defective expression of R2B in all cortisol-secreting adenomas (n = 16) compared with the normal counterpart, while both R1A and R2A were expressed at high levels in the same tissues. Conversely, carcinomas (n = 5) showed high levels of all subunits. Sequencing of R1A and R2B genes revealed a wild type sequence in all tissues. The effect of R1/R2 ratio on proliferation was assessed in mouse adrenocortical Y-1 cells. The R2-selective cAMP analogue 8-Cl-cAMP dose-dependently inhibited Y-1 cell proliferation and induced apoptosis, while the R1-selective cAMP analogue 8-HA-cAMP stimulated cell proliferation. Finally, R2B gene silencing induced up-regulation of R1A protein, associated with an increase in cell proliferation. Inmore » conclusion, we propose that a high R1/R2 ratio favors the proliferation of well differentiated and hormone producing adrenocortical cells, while unbalanced expression of these subunits is not required for malignant transformation.« less
Authors:
; ; ; ;  [1] ; ;  [2] ;  [3] ;  [4] ;  [2] ;  [1] ;  [5]
  1. Endocrine Unit, Department of Medical Sciences, University of Milan, Fondazione Policlinico IRCCS, Milan (Italy)
  2. Pathology Unit, Department of Medicine, Surgery and Dentistry, A.O. San Paolo and Fondazione Policlinico IRCCS, University of Milan (Italy)
  3. Endocrine Surgery, Fondazione Ospedale Maggiore Policlinico IRCCS, Milan (Italy)
  4. Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona (Italy)
  5. Endocrine Unit, Department of Medical Sciences, University of Milan, Fondazione Policlinico IRCCS, Milan (Italy), E-mail: anna.spada@unimi.it
Publication Date:
OSTI Identifier:
21045922
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 314; Journal Issue: 1; Other Information: DOI: 10.1016/j.yexcr.2007.08.024; PII: S0014-4827(07)00410-7; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACTH; ADENOMAS; AMP; APOPTOSIS; CELL PROLIFERATION; GENES; GROWTH; HYDROCORTISONE; MICE; MUTATIONS