Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity.

Abstract

Objective: The cAMP/protein kinase A (PKA) pathway plays an important role in endocrine tumorigenesis. PKA is a heterotetramer with two regulatory subunits (four genes: PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B) and two catalytic subunits. Inactivating PRKAR1A mutations have been observed in Carney complex and a subset of adrenocortical tumors (ACT). This study was designed to search for other alterations of PKA in ACT, and to establish their correlation with the clinical characteristics. Methods: In this study, 35 ACT (10 non-secreting adrenocortical adenomas (ACA-NS), 13 cortisolsecreting adenomas (ACA-S), and 12 malignant s (ACC)) were studied. PKA subunits were studied by western blot and RT-qPCR. The PKA activity was measured. Results: A subgroup of ACA-S with a 96% R2B protein decrease by comparison with normal adrenal (4.1%G4 vs 100%G19, P!0.001) was identified, ACA-S2 (6/13). By contrast, no differences were observed in ACC and ACA-NS. The level of R1A mRNA was decreased in ACA-S (P!0.001), but not the level of R2B mRNA. No mutation of the R2B gene was detected in ACA-S2. The ACA-S2 group with loss of R2B protein showed a threefold higher basal PKA activity than the ACA with normal R2B protein (3.37G0.31 vs 1.00G0.20, P!0.0001). The ACA-S2 tumors with the loss of the R2B protein presented a homogenous phenotype and were all small benign cortisol-secreting tumors. Conclusion: This loss of PRKAR2B protein due to a post-transcriptional mechanism in ACA-S is a new mechanism of cAMP pathway dysregulation in adrenocortical tumorigenesis. It defines a new subtype of secreting adenomas with high basal PKA activity presenting a homogenous clinical phenotype.European Journal of Endocrinology 158 829-839

Differential expression of the protein kinase A subunits in normal adrenal glands and adrenocortical adenomas

“…Thus, it remains unclear if the expression of the regulatory subunits influences the specific steroidogenic profile of the three zones of the adrenal cortex. Of note, in some CPA, reduced protein levels of the regulatory subunit IIβ have been previously observed 23, 24 . Here we investigate if the PRKACA mutations leading to hyperactivity of PKA signalling in CPA are associated with the loss of RIIβ protein levels and demonstrate a clear connection between RIIβ protein levels and the mutation status of PRKACA .…”

“…In 2008 two studies had shown that protein expression of the RIIβ subunit of PKA is markedly reduced in CPA compared to other adrenocortical tumours, while no such differences were observed regarding the expression of the other regulatory subunits 23, 24 . There were some discrepancies between the two studies, with Mantovani et al .…”

“…Therefore, we assessed the protein levels of PKA subunits by both immunohistochemistry and immunoblotting in a large series of adrenocortical tumours with known PRKACA mutation status, including 10 samples that had already been included in the study by Vincent-Dejean et al . 23 .…”

“…In addition, 15 FFPE tissues from normal adrenal glands from patients that underwent adrenalectomy due to kidney tumours were consecutively collected at the University Hospital Wuerzburg. Furthermore, fresh frozen tissues of 34 CPA were collected consecutively at the University Hospitals of Wuerzburg (n = 15) and Munich (n = 9), and the Hôpital Cochin Paris (n = 10) 23 for mRNA and protein analyses. All patients gave informed consent and the study was approved by the Ethics Comities of the University Hospitals of Wuerzburg, Munich and Padua and the Institute Cochin Paris.…”

Investigation of ErbB and Insulin Signaling Pathways in the Pathogenesis of Multiple Myeloma

“…Our results are matching with Neben and et al results. Expression increase in breast, colorectal and various human nonendocrine cancers (26) and especially in cervical cancer this increased expression is related with poor prognosis. In our study, we determined that PRKAR2A gene is 5 times expressed; also there aren't any studies, which reveal this gene's relation with MM.…”