title: Acceleration of the glycolytic flux by steroid receptor coactivator-2 is essential for endometrial decidualization.
abstract: Early embryo miscarriage is linked to inadequate endometrial decidualization, a cellular transformation process that enables deep blastocyst invasion into the maternal compartment. Although much of the cellular events that underpin endometrial stromal cell (ESC) decidualization are well recognized, the individual gene(s) and molecular pathways that drive the initiation and progression of this process remain elusive. Using a genetic mouse model and a primary human ESC culture model, we demonstrate that steroid receptor coactivator-2 (SRC-2) is indispensable for rapid steroid hormone-dependent proliferation of ESCs, a critical cell-division step which precedes ESC terminal differentiation into decidual cells. We reveal that SRC-2 is required for increasing the glycolytic flux in human ESCs, which enables rapid proliferation to occur during the early stages of the decidualization program. Specifically, SRC-2 increases the glycolytic flux through induction of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3), a major rate-limiting glycolytic enzyme. Similarly, acute treatment of mice with a small molecule inhibitor of PFKFB3 significantly suppressed the ability of these animals to exhibit an endometrial decidual response. Together, these data strongly support a conserved mechanism of action by which SRC-2 accelerates the glycolytic flux through PFKFB3 induction to provide the necessary bioenergy and biomass to meet the demands of a high proliferation rate observed in ESCs prior to their differentiation into decidual cells. Because deregulation of endometrial SRC-2 expression has been associated with common gynecological disorders of reproductive-age women, this signaling pathway, involving SRC-2 and PFKFB3, promises to offer new clinical approaches in the diagnosis and/or treatment of a non-receptive uterus in patients presenting idiopathic infertility, recurrent early pregnancy loss, or increased time to pregnancy.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Kommagani
authors.forename: Maria M
authors.initials: MM
authors.lastname: Szwarc
authors.forename: Ertug
authors.initials: E
authors.lastname: Kovanci
authors.forename: William E
authors.initials: WE
authors.lastname: Gibbons
authors.forename: Nagireddy
authors.initials: N
authors.lastname: Putluri
authors.forename: Suman
authors.initials: S
authors.lastname: Maity
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Arun
authors.initials: A
authors.lastname: Sreekumar
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D000022:Abortion, Spontaneous / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D003656:Decidua / Q000166:cytology / Q000378:metabolism; D010064:Embryo Implantation / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics* / Q000378:metabolism; D025481:Phosphofructokinase-2 / Q000096:biosynthesis* / Q000235:genetics; D011247:Pregnancy; D015398:Signal Transduction / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D051958:Nuclear Receptor Coactivator 2; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2