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.

Warburg-like Glycolysis and Lactate Shuttle in Mouse Decidua during Early Pregnancy

“…Pdk4, which has a similar property as Pdk1, is also induced in human decidualizing cells (36). Besides, an accelerated glycolytic flux is essentially required for decidualization in both mice and humans (4).…”

“…In this study, knocking down Pkm2 or injecting 3-bromopyruvate to disrupt glycolysis can impair decidualization. Consistently, drugs targeting glycolysis could hamper decidualization in both humans and rodents (4). Therefore, Warburg-like glycolysis is essential for decidualizing cells to ensure enough bioenergy and biosynthesis during early pregnancy.…”

“…Compromised decidualization is an essential reason for pregnancy failures, 75% of which are associated with the defects that occur during peri-implantation periods in humans (2). Several studies have shown activated glucose metabolism for human decidualization (3,4). The activity of glycolysis is also promoted in rodent decidua (5,6).…”

“…The activity of glycolysis is also promoted in rodent decidua (5,6). Now, it has been determined that glycolysis plays critical roles during decidualization in both rodents and humans (3,4,7,8). However, how glucose metabolism is regulated in decidua and the functions of glycolysis during decidualization both remain unclear.…”

“…Collectively, our findings provide fundamental insights into glycolysis and lactate communication in endometrium during mouse decidualization. In humans, decidualization also requires enhanced glycolysis (4). Abnormal glucose metabolism in human uterus is associated with several pregnancy complications, and also exists in patients with poor fertility (8, 18 -20).…”