Effects of phosphorylated estrogen receptor alpha on apoptosis in human endometrial epithelial cells

It is known that the activities of estrogen receptor alpha (ER alpha) can be modulated by epidermal growth factor (EGF) through the phosphatidylinostitol 3-kinase-alpha serine/threonine protein kinase (PI3K-AKT) pathway by phosphorylation. To clarify how ER alpha functions are regulated in endometrial cells during menstrual cycle, molecules related to phosphorylation of ER alpha (pER alpha) were examined. It was found that the expression of phosphorylated AKT on serine 473 (pAKT-Ser473) was increased during the proliferative phase, but decreased in the secretory phase. Although the expression of pAKT on threonine 308 in the proliferative phase was only identified in the wall of arterioles, it was strongly expressed in the cytoplasm of endometrial glandular cells after entering the secretory phase. Further observations revealed that while the expression of pER alpha-Ser104 was constant, pER alpha-Ser118 was expressed following a cyclic pattern similar to that of the pAKT-Ser473. Following treatment with specific inhibitors for EGFR-PI3K-AKT pathway, it was found that while the expression of pER alpha-Ser118 and pER alpha-Ser167 was inhibited, the induced apoptosis could be antagonized by the addition of estrogen, indicating that a mitochondrial pathway is involved. Therefore, pAKT and pER alpha or ER alpha could act cooperatively on coiled arterioles and endometrial cells in order to control menstrual cycle.