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CAMP/PKA signaling promotes AKT deactivation via reducing CIP2A expression, thereby facilitating decidualization

ABSTRACT: Decidualization is a progesterone-initiated differentiation concerning the endometrium and is dedicated to supporting the placenta and embryo development. During the process, cAMP signaling is widely known to be indispensable, but the details are not fully understood. In this study, we show that cAMP signaling promotes AKT deactivation in endometrial stromal cells, which favors their decidualization. The deactivation of AKT is found to be a consequence of the reduced expression of several inhibitors of PP2A, the major phosphatase of AKT, with CIP2A being the most prominent. To show that CIP2A loss is obligatory for decidualization, we performed this ATAC-seq analysis. Persistent CIP2A expression impairs the chromatin accesibility remodeling during decidualization.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224212 | GEO | 2023/02/06

REPOSITORIES: GEO

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Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype

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The PKA Pathway of Endometrial Stromal Fibroblasts Reveals Differentiation and Proliferative Potential in Endometriosis

Project description:Intrinsic abnormalities in transplanted eutopic endometrium are believed to contribute to the pathogenesis of pelvic endometriosis. Herein, we investigated transcriptomic differences in human endometrial stromal fibroblasts (hESF) from women with (hESFendo) versus without (hESFnon-endo) endometriosis, in response to activation of the PKA pathway with 8-Br-cAMP. hESFnon-endo (n=4) and hESFendo (mild endometriosis, n=4) were isolated from eutopic endometrium and treated +/- 0.5mM 8-Br-cAMP for 96 hours. Purified total RNA was subjected to microarray analysis using the whole genome Gene 1.0 ST Affymetrix platform. 733 genes were regulated in cAMP-treated hESFnon-endo versus 172 genes in hESFendo, suggesting a blunted response to cAMP/PKA pathway activation in women with disease. Real-time PCR and ELISA validated the decreased expression of decidualization markers in hESFendo compared to hESFnon-endo. In the absence of disease, 8-Br-cAMP down-regulated progression through the cell-cycle due to a decrease in Cyclin D1, cyclin-dependent kinase 6 and cell division cycle 2, and an increase in cyclin-dependent kinase inhibitor 1A. However, cell cycle components in hESFendo were not responsive to 8-Br-cAMP, resulting in persistence of a proliferative phenotype. hESFendo treated with 8-Br-cAMP exhibited altered expression of immune response, extracellular matrix, cytoskeleton, and apoptosis genes. Changes in phosphodiesterase expression and activity were not different among experimental groups. Thus, eutopic hESF with increased proliferative potential may seed the pelvic cavity via retrograde menstruation and promote establishment, survival, and proliferation of endometriosis lesions, independent of hydrolysis of cAMP and likely due to an inherent abnormality in the PKA pathway in the presence of disease.

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