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

Salama A. Salama, Mahmoud A. Mohammad, Concepcion R. Diaz-Arrastia, Marwa W. Kamel, Gokhan Kilic, Bih T. Ndofor, Mohamed S. Abdel-Baki, Shaleen K. Theiler

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

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.

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 nucleartranslocation. 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 ERa 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 ERa and small-molecule PKM2 activators inhibit ERα transcriptional activity and reduce E2-induced cell proliferation.

Original languageEnglish (US)
Pages (from-to)3790-3799
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number10
DOIs
StatePublished - Oct 1 2014

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Pyruvate Kinase
Stromal Cells
Metabolism
Estrogen Receptors
Estradiol
Up-Regulation
Cell proliferation
Cell Proliferation
Glucose
Heterogeneous-Nuclear Ribonucleoproteins
Smegmamorpha
Phosphorylation
Molecules
Acidification
Glycolysis
Immunoblotting
Oxygen Consumption
Energy Metabolism
Oxidation-Reduction
Real-Time Polymerase Chain Reaction

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Estradiol-17β upregulates pyruvate kinase M2 expression to coactivate estrogen receptor-α and to integrate metabolic reprogramming with the mitogenic response in endometrial cells. / Salama, Salama A.; Mohammad, Mahmoud A.; Diaz-Arrastia, Concepcion R.; Kamel, Marwa W.; Kilic, Gokhan; Ndofor, Bih T.; Abdel-Baki, Mohamed S.; Theiler, Shaleen K.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 99, No. 10, 01.10.2014, p. 3790-3799.

Research output: Contribution to journalArticle

Salama, Salama A. ; Mohammad, Mahmoud A. ; Diaz-Arrastia, Concepcion R. ; Kamel, Marwa W. ; Kilic, Gokhan ; Ndofor, Bih T. ; Abdel-Baki, Mohamed S. ; Theiler, Shaleen K. / Estradiol-17β upregulates pyruvate kinase M2 expression to coactivate estrogen receptor-α and to integrate metabolic reprogramming with the mitogenic response in endometrial cells. In: Journal of Clinical Endocrinology and Metabolism. 2014 ; Vol. 99, No. 10. pp. 3790-3799.
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abstract = "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.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.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 nucleartranslocation. 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 ERa 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 ERa and small-molecule PKM2 activators inhibit ERα transcriptional activity and reduce E2-induced cell proliferation.",
author = "Salama, {Salama A.} and Mohammad, {Mahmoud A.} and Diaz-Arrastia, {Concepcion R.} and Kamel, {Marwa W.} and Gokhan Kilic and Ndofor, {Bih T.} and Abdel-Baki, {Mohamed S.} and Theiler, {Shaleen K.}",
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T1 - Estradiol-17β upregulates pyruvate kinase M2 expression to coactivate estrogen receptor-α and to integrate metabolic reprogramming with the mitogenic response in endometrial cells

AU - Salama, Salama A.

AU - Mohammad, Mahmoud A.

AU - Diaz-Arrastia, Concepcion R.

AU - Kamel, Marwa W.

AU - Kilic, Gokhan

AU - Ndofor, Bih T.

AU - Abdel-Baki, Mohamed S.

AU - Theiler, Shaleen K.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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.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.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 nucleartranslocation. 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 ERa 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 ERa and small-molecule PKM2 activators inhibit ERα transcriptional activity and reduce E2-induced cell proliferation.

AB - 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.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.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 nucleartranslocation. 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 ERa 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 ERa and small-molecule PKM2 activators inhibit ERα transcriptional activity and reduce E2-induced cell proliferation.

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