Estradiol-17β upregulates pyruvate kinase M2 expression to coactivate estrogen receptor-α and to integrate metabolic reprogramming with the mitogenic response in endometrial cells.

CONTEXT: Proliferating cells reprogram their cellular glucose metabolism to meet the bioenergetic and biosynthetic demands and to maintain cellular redox homeostasis. Pyruvate kinase M (PKM) is a critical regulator of this metabolic reprogramming. However, whether estradiol-17β (E2) reprograms cellular metabolism to support proliferation of human primary endometrial stromal cells (hESCs) and the molecular basis of this reprogramming are not well understood.
OBJECTIVES: Our objectives were to study whether E2 induces reprogramming of glucose metabolism in hESCs and to investigate the potential roles of PKM2 in E2-induced metabolic reprogramming and proliferation of these cells.
METHODS: The oxygen consumption rate and extracellular acidification rate were assessed by a Seahorse XF24 analyzer. PKM2 expression was assessed by real-time RT-PCR and immunoblotting.
RESULTS: E2 induces a Warburg-like glucose metabolism in hESCs by inducing the expression of PKM. E2 also enhanced PKM splicing into the PKM2 isoform by upregulating the c-Myc-hnRNP axis. Furthermore, E2 induces PKM2 oxidation, phosphorylation, and nuclear translocation. In addition to its glycolytic function, PKM2 physically interacted with estrogen receptor-α (ERα) and functioned as an ERα coactivator. Small-molecule PKM2 activators ameliorated ERα transcriptional activity and abrogated the E2-induced hESC proliferation.
CONCLUSIONS: We show for the first time that E2-induced hESC proliferation is associated with a shift in glucose metabolism toward aerobic glycolysis, and the molecular basis for this metabolic shift is linked to the effects of E2 on PKM2. In addition, PKM2 acts as a transcriptional coactivator for ERα and small-molecule PKM2 activators inhibit ERα transcriptional activity and reduce E2-induced cell proliferation.