Estradiol-17β upregulates pyruvate kinase M2 expression to coactivate estrogen receptor-α and to integrate metabolic reprogramming with the mitogenic response in endometrial cells.
| Autor: | Salama SA; 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., Mohammad MA, Diaz-Arrastia CR, Kamel MW, Kilic GS, Ndofor BT, Abdel-Baki MS, Theiler SK |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2014 Oct; Vol. 99 (10), pp. 3790-9. Date of Electronic Publication: 2014 Jan 28. |
| DOI: | 10.1210/jc.2013-2639 |
| Abstrakt: | 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. |
| Databáze: | MEDLINE |
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