title: Increased activation of the PI3K/AKT pathway compromises decidualization of stromal cells from endometriosis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Division of Reproductive Biology Research, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Xunqin
authors.initials: X
authors.lastname: Yin
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Pavone
authors.forename: Zhenxiao
authors.initials: Z
authors.lastname: Lu
authors.forename: JianJun
authors.initials: J
authors.lastname: Wei
authors.forename: J Julie
authors.initials: JJ
authors.lastname: Kim
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D010064:Embryo Implantation / Q000235:genetics / Q000502:physiology; D004715:Endometriosis / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D010049:Ovarian Diseases / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D017154:Stromal Cells / Q000473:pathology / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
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