cAMP signaling in cortisol-producing adrenal adenoma

Abstract

The cAMP signaling pathway is one of the major players in the regulation of growth and hormonal secretion in adrenocortical cells. Although its role in the pathogenesis of adrenocortical hyperplasia associated with Cushing's syndrome has been clarified, a clear involvement of the cAMP signaling pathway and of one of its major downstream effectors, the protein kinase A (PKA), in sporadic adrenocortical adenomas remained elusive until recently. During the last year, a report by our group and three additional independent groups showed that somatic mutations of PRKACA, the gene coding for the catalytic subunit a of PKA, are a common genetic alteration in patients with Cushing's syndrome due to adrenal adenomas, occurring in 35-65% of the patients. In vitro studies revealed that those mutations are able to disrupt the association between catalytic and regulatory subunits of PKA, leading to a cAMP-independent activity of the enzyme. Despite somatic PRKACA mutations being a common finding in patients with clinically manifest Cushing's syndrome, the pathogenesis of adrenocortical adenomas associated with subclinical hypercortisolism seems to rely on a different molecular background. In this review, the role of cAMP/PKA signaling in the regulation of adrenocortical cell function and its alterations in cortisolproducing adrenocortical adenomas will be summarized, with particular focus on recent developments.

Double adrenocortical adenomas harboring independent KCNJ5 and PRKACA somatic mutations

“…The p.L206R mutation is located in a highly conserved core of the domain responsible for the interaction between the regulatory and catalytic subunits of PKA (7). Functional experiments revealed that the mutation caused constitutive PKA activation, providing a molecular explanation for the development of CPA (7, 8). The mutation analysis suggests that the CYP11B2 positive tumor was the main source of autonomous aldosterone production and the CYP11B2 negative and CYP17 positive tumor was the main source of autonomous cortisol production in this case.…”

“…More recently, recurrent activating mutations in PRKACA , encoding the catalytic subunit α of protein kinase A (PKA) have been identified in CPA (7). PRKACA gene mutations are found in 35-65% of the patients with CS (8). Herein, we report a case of PA and CS due to the co-existence of two adenomas harboring novel KCNJ5 somatic mutations and a PRKACA somatic mutation.…”

Activating PRKACB somatic mutation in cortisol-producing adenomas

“…Beyond the typical clinical picture, overt CS is associated with severe comorbidities and increased mortality (22,23). Patients whose tumors harbor PRKACA mutations present at a younger age at diagnosis, higher cortisol levels, and, interestingly, smaller-size tumors than CPAs without mutations (24,25).…”

Predicting cancer-relevant proteins using an improved molecular similarity ensemble approach

“…The protein hydrolyzes both cAMP and cGMP, regulating the intracellular concentration of cyclic nucleotides in the striatum [42]. As a target for signal transduction regulation, it has not been reported to have anticancereffects; however, cAMP mediates the translation of cancer cells into healthy cells [43, 44]. …”