Effect of cyclic adenosine 3′,5′-monophosphate/protein kinase A pathway on markers of cell proliferation in nonfunctioning pituitary adenomas

G. Mantovani, S. Bondioni, S. Ferrero, B. Gamba, E. Ferrante, E. Peverelli, S. Corbetta, M. Locatelli, P. Rampini, P. Beck-Peccoz, A. Spada, A. G. Lania

Research output: Contribution to journalArticlepeer-review

Abstract

Context: Alterations in cAMP signaling have been identified as a cause of endocrine neoplasia. In particular, activating mutations of the G sα gene and protein kinase A (PKA) overactivity due to low expression of PKA regulatory subunit 1A (R1A) have been implicated in somatotroph proliferation. Objective: The objective of this study was to evaluate the effects of cAMP-PKA cascade activation in nonfunctioning pituitary adenomas (NFPA). Design and Methods: By immunohistochemistry, R1A, R2A, and R2B expression was evaluated in cells obtained from eight surgically removed NFPA positive for gonadotropins. Cyclin D1 expression and ERK1/2 activity were analyzed under basal conditions and after cAMP-PKA cascade activation. Results: Immunohistochemistry studies demonstrated a low R1/R2 ratio in all NFPA. Additional unbalance of R1/R2 ratio by 8-chloroadenosine cAMP (8-Cl-cAMP) and direct adenylyl cyclase stimulation by forskolin did not increase cyclin D1 expression or ERK1/2 activity in five NFPA (group 1), but even caused 74 ± 15% and 85 ± 13% inhibitions of cyclin D1 and ERK1/2 activity, respectively, in the remaining NFPA (group 2). Moreover, in group 2, PKA blockade by the specific inhibitor PKI increased cyclin D1 expression (96 ± 25% over basal) and ERK1/2 activity (116 ± 28% over basal). Conclusions: These data show that in contrast with what was previously observed in transformed somatotrophs, activation of the cAMP-PKA pathway did not generate proliferative signals in tumoral cells of the gonadotroph lineage, and in a subset of tumors even exerted a tonic inhibitory effect, thus confirming a different role for the cAMP-mediated pathway in promoting proliferation in the pituitary.

Original languageEnglish
Pages (from-to)6721-6724
Number of pages4
JournalJournal of Clinical Endocrinology and Metabolism
Volume90
Issue number12
DOIs
Publication statusPublished - Dec 2005

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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