In Vivo and In Vitro Regulation of Akt Activation in Human Endometrial Cells Is Estrogen Dependent

• Published in: Biology of reproduction Vol. 71; no. 3; pp. 714 - 721
• Main Authors: Kayisli, Ozlem Guzeloglu, Kayisli, Umit A, Luleci, Guven, Arici, Aydin
• Format: Journal Article
• Language: English
• Published: Madison, WI Society for the Study of Reproduction 01.09.2004
• Subjects: Adenocarcinoma; Biological and medical sciences; Blotting, Western; Breast Neoplasms; Cell Division - drug effects; Cell Division - physiology; Cell Line, Tumor; Cell Nucleus - metabolism; Contents; early development; Embryology: invertebrates and vertebrates. Teratology; Endometrial Neoplasms; Endometrium - cytology; Endometrium - metabolism; estradiol; Estradiol - pharmacology; Estrogen Antagonists - pharmacology; Female; female reproductive tract; Fetal membranes; Fundamental and applied biological sciences. Psychology; General aspects. Development. Fetal membranes; Humans; Immunohistochemistry; In Vitro Techniques; menstrual cycle; Menstrual Cycle - metabolism; Mutation; phosphatases; Phosphoric Monoester Hydrolases - genetics; Phosphorylation; Pregnancy; Pregnancy Trimester, First; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction - drug effects; Signal Transduction - physiology; Stromal Cells - cytology; Stromal Cells - drug effects; Stromal Cells - metabolism; Tumor Suppressor Proteins - genetics; Vertebrates: reproduction; Human; In vivo; Reproduction; Uterus; Female genital system; Estrogen; Sex steroid hormone; In vitro; Ovarian hormone; Endometrium
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod.104.027235

Estrogen-bound estrogen receptors (ER) α and β classically activate gene expression after binding to the estrogen response element in the promoter regions of target genes. Estrogen also has rapid, nongenomic effects. It activates several membranous or cytoplasmic kinase cascades, including the phosphatidylinositol 3-phosphate (PI3K/Akt) cascade, a signaling pathway that plays a key role in cell survival and apoptosis. Normal human endometrium is exposed to variable levels of steroid hormones throughout the menstrual cycle. We hypothesized that Akt phosphorylation in human endometrium may vary with the menstrual cycle and in early pregnancy and that fluctuations in estrogen level may play a role in Akt activation in endometrial cells. We analyzed Akt phosphorylation using in vivo and in vitro techniques, including Western blot, immunohistochemistry, and immunocytochemistry. Estradiol significantly increased Akt phosphorylation in endometrial cells. Rapid stimulation of Akt activation in cultured stromal cells was observed. Akt phosphorylation by estradiol was inhibited by the PI3K inhibitor, wortmannin, but not by the ER antagonist, ICI 182 780. The maximal effect on Akt activity was observed following 5–15 min of estradiol treatment. Our results suggest that estradiol may directly affect PI3K-related signaling pathway by increasing the phosphorylation of Akt in endometrial cells. Thus, estradiol may exert part of its proliferative and antiapoptotic effects by a nongenomic manner through the Akt signaling pathway.