cAMP signaling systems play a critical role in regulation of thyroid cell proliferation and function. Besides the well known protein kinase A (PKA) cascade, Epac (exchange protein directly activated by cAMP) depicts a novel effector of cAMP. Epac is directly activated by cAMP and in turn stimulates kinase cascades like Akt kinase, phospholipase Cε and MAP kinases as well as the Ras-like GTPases Rap1 and Rap2. As data about the impact of Epac on cAMP signaling of thyroid cells are limited, we studied whether Epac may be involved in the signaling network of thyroid cells and thyroid tumors.
In thyroid carcinoma tissues, we showed a strong expression of Epac1 in aggressive subtypes of thyroid carcinomas: a more intense immunohistochemical staining was determined in tall cell papillary thyroid carcinomas (PTC) compared to follicular and classical PTC subtypes. Expression in follicular thyroid carcinomas (FTC) was more intense in oxyphilic types compared to non-oxyphilic FTCs. The role of Epac activation in thyroid cell models was studied using the Epac-specific cAMP analog 8-pCPT-2′-O-Me-cAMP. During stimulation with this cAMP analog, proliferation of the normal thyroid cell line FRTL5 as well as of the thyroid carcinoma cell lines FTC133 and SW1736 was enhanced, while proliferation of HTh74 thyroid carcinoma cells was not significantly affected. In FRTL5 cells, the proliferation-promoting effect was enhanced by the presence of calf serum or H5-hormone mix implicating a network of distinct signaling pathways. Using Rap-pull down assays with immobilized GST-Ras/Rap binding domain of RalGDS we additionally found that Epac activates the Ras-like GTPases Rap1 and Rap2 in FRTL5, FTC133, SW1736 and HTh74 cells.
In conclusion, Epac-dependent pathways are functionally active in thyroid cells and thyroid carcinoma cells and thus may contribute to regulation of proliferation and function of these cells by cAMP.
01 - 05 Apr 2006
European Society of Endocrinology