Increased Activation of the PI3K/AKT Pathway Compromises Decidualization of Stromal Cells from Endometriosis

Yin X, Xunqin Yin, Mary Ellen Pavone, Zhenxiao Lu, Lu Z, Wei J, JianJun Wei, Jian-Jun Wei, Julie Kim, J Julie Kim
The Journal of clinical endocrinology and metabolism · 2011 · vol. 97(1) , pp. E35–E43 · doi:10.1210/jc.2011-1527 · PMID:22072736 · PMC3251935 · W2057772370
article OA: bronze CC0 ⤵ 104 in-corpus citations
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Endometriotic stromal cells exhibit increased PI3K/AKT pathway activation, leading to reduced nuclear FOXO1 and compromised decidualization gene expression compared to normal endometrial cells.

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Abstract

CONTEXT: Endometriosis affects approximately 10% of women in the United States and causes pain and infertility. Decidualization of endometrial stromal cells from women with endometriosis is aberrant. OBJECTIVE: The objective of this study was to investigate a potential mechanism for the inadequate decidual response in stromal cells from ovarian endometriomas. DESIGN: Stromal cells of the endometrium from women without endometriosis (HSC) or from ovarian endometriomas (OsisSC) were grown in culture and treated with 10 μm LY294002 or 250 nm MK2206, 100 nm medroxyprogesterone acetate (M), and 0.5 mm dibutyryl cAMP (A) or infection with 100 multiplicity of infection adenoviral constructs containing wild-type Forkhead box O1 or triple-mutant FOXO1. Real-time PCR was used to measure the expression of FOXO1, IGF binding protein-1 (IGFBP1), and prolactin (PRL) mRNA, and Western blot and immunohistochemical staining were used to detect the levels of progesterone receptor (PR), FOXO1, AKT, and p(Ser473)-AKT protein in vitro or in vivo. RESULTS: Expression of the decidua-specific genes, IGFBP1 and PRL, were significantly lower in OsisSC compared with normal HSC in response to M+A treatment. Basal expression levels of PRA, PRB, and FOXO1 proteins were dramatically lower in OsisSC. Overexpression of triple-mutant FOXO1 increased mRNA levels of IGFBP1 and PRL in OsisSC in the presence of M+A, whereas the overexpression of wild-type FOXO1 had no effect. AKT was highly phosphorylated in OsisSC compared with HSC and inhibition of phosphatidylinositol 3-kinase, with LY294002, increased levels of FOXO1 protein as well as IGFBP1 mRNA in the presence of M+A. Moreover, inhibition of AKT with MK2206, an allosteric AKT inhibitor, dramatically increased the accumulation of nuclear FOXO1 as well as expression of IGFBP1. Finally, immunohistochemical staining demonstrated higher p(Ser473)-AKT and lower FOXO1 levels in endometriosis tissues, compared with normal endometrial tissues. CONCLUSIONS: In endometriotic stromal cells, overactivation of the phosphatidylinositol 3-kinase/AKT signaling pathway contributes to the reduced expression of the decidua-specific gene, IGFBP1, potentially through reduced levels of nuclear FOXO1.

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Condition tags

endometriosisinfertility

MeSH descriptors

Embryo Implantation Embryo Implantation Embryo Implantation Endometriosis Ovarian Diseases Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt Stromal Cells Cell Nucleus Cell Nucleus Cells, Cultured Down-Regulation Endometriosis Endometriosis Enzyme Activation Female Forkhead Box Protein O1 Forkhead Transcription Factors Forkhead Transcription Factors Gene Expression Regulation

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