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


OBJECTIVE
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.
Department of Obstetrics and Gynecology (S.A.S., C.R.D.-A., B.T.N.), Division of Gynecologic Oncology; Department of Pediatrics (M.A.M.), Children's Nutrition Research Center, U.S. Department of Agriculture/Agricultural Research Service; and Department of Pediatric Hematology-Oncology (M.S.A.-B.), Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030; Department of Tumor Biology (M.W.K.), Unit of Pharmacology, National Cancer Institute, Cairo University, Egypt; and Department of Obstetrics and Gynecology (G.S.K.), University of Texas Medical Branch, Galveston, Texas 77555; and Section of Biostatistics and Epidemiology (S.K.T.), Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03755.
Salama A
SA
Salama
Mahmoud A
MA
Mohammad
Concepcion R
CR
Diaz-Arrastia
Marwa W
MW
Kamel
Gokhan S
GS
Kilic
Bih T
BT
Ndofor
Mohamed S
MS
Abdel-Baki
Shaleen K
SK
Theiler
D017398:Alternative Splicing / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D065150:Cellular Reprogramming / Q000187:drug effects / Q000502:physiology; D004717:Endometrium / Q000166:cytology; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008934:Mitogens / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D061251:Primary Cell Culture; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008934:Mitogens; D019344:Lactic Acid; D004958:Estradiol; D011770:Pyruvate Kinase; D005947:Glucose