How does cAMP/protein kinase A signaling lead to tumors in the adrenal cortex and other tissues?

Abstract

The overwhelming majority of benign lesions of the adrenal cortex leading to Cushing syndrome are linked to one or another abnormality of the cAMP signaling pathway. A small number of both massive macronodular adrenocortical disease and cortisol-producing adenomas harbor somatic GNAS mutations. Micronodular adrenocortical hyperplasias are either pigmented (the classic form being that of primary pigmented nodular adrenocortical disease) or non-pigmented; micronodular adrenocortical hyperplasias can be seen in the context of other conditions or isolated; for example, primary pigmented nodular adrenocortical disease usually occurs in the context of Carney complex, but isolated primary pigmented nodular adrenocortical disease has also been described. Both Carney complex and isolated primary pigmented nodular adrenocortical disease are caused by germline PRKAR1A mutations; somatic mutations of this gene that regulates cAMP-dependent protein kinase are also found in cortisol-producing adenomas, and abnormalities of PKA are present in most cases of massive macronodular adrenocortical disease. Micronodular adrenocortical hyperplasias and some cortisol-producing adenomas are associated with phosphodiesterase 11A and 8B defects, coded, respectively, by the PDE11A and PDE8B genes. Mouse models of Prkar1a deficiency also show that increased cAMP signaling leads to tumors in adrenal cortex and other tissues. In this review, we summarize all recent data from ours and other laboratories, supporting the view that Wnt-signaling acts as an important mediator of tumorigenicity induced by abnormal PRKAR1A function and aberrant cAMP signaling.

Figure 1

Pituitary (A) and thyroid (B) gland tumors in Prkar1a^+/- Rb1^+/- mice. Prkar1a^+/-Rb1^+/- mice also developed more pituitary tumors and medullary thyroid carcinomas than Rb1^+/- mice. Over-expression of β-catenin in pituitary (C) and thyroid (D) tumors from Prkar1a^+/- Rb1^+/- mice.

Figure 2

A. Prkar1a^+/- mice developed significantly more skin papillomas than wild-type animals after treatment with a skin carcinogenesis protocol. B. Strong staining of Lrp5 and β-catenin in papillomas from Prkar1a^+/- mice.

Figure 3

Schematic representation of Wnt signaling pathway activation in R1α deficient tumor cells. Wnt signaling enrichment was demonstrated in human and mouse tumors associated with cAMP/PKA activation. Up-regulation of WNT3, WNT3A, WNT7 and WISP2 induces the activation of the β-catenin-dependent signaling (canonical pathway). Binding of Wnt ligands to the frizzled, LRP5, and LRP6 receptors inhibits the degradation of β-catenin cytoplasmic complex and leads to nuclear accumulation of β-catenin. CTNNB1 mutations in adrenal tumors also promote β-catenin stabilization. miR-449 is one of the highest down-regulated microRNAs in PPNAD and regulates WISP2 expression. WNT, Wingless-type MMTV integration site family; DKK, Dickkopf; WISP2, WNT1-inducible signaling pathway protein 2; LRP5, low-density lipoprotein receptor-related protein 5; DVL, Dishevelled; APC, activated protein C; GSK3β, glycogen synthase kinase 3 beta; LEF/TCF, lymphoid enhancer factor/T-cell factor; PKA, protein kinase A; PPNAD, primary pigmented nodular adrenocortical disease.