Estrogen activates pyruvate kinase M2 and increases the growth of TSC2-deficient cells
Identifieur interne : 000149 ( Pmc/Checkpoint ); précédent : 000148; suivant : 000150Estrogen activates pyruvate kinase M2 and increases the growth of TSC2-deficient cells
Auteurs : Yiyang Lu [États-Unis] ; Xiaolei Liu [États-Unis] ; Erik Zhang [États-Unis] ; Elizabeth J. Kopras [États-Unis] ; Eric P. Smith [États-Unis] ; Aristotelis Astreinidis [États-Unis] ; Chenggang Li [États-Unis, République populaire de Chine] ; Yuet-Kin Leung [États-Unis] ; Shuk-Mei Ho [États-Unis] ; Jane J. Yu [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2020.
Abstract
Lymphangioleiomyomatosis (LAM) is a devastating lung disease caused by inactivating gene mutations in either
Url:
DOI: 10.1371/journal.pone.0228894
PubMed: 32078667
PubMed Central: 7032738
Affiliations:
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<front><div type="abstract" xml:lang="en"><p>Lymphangioleiomyomatosis (LAM) is a devastating lung disease caused by inactivating gene mutations in either <italic>TSC1</italic>
or <italic>TSC2</italic>
that result in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). As LAM occurs predominantly in women during their reproductive age and is exacerbated by pregnancy, the female hormonal environment, and in particular estrogen, is implicated in LAM pathogenesis and progression. However, detailed underlying molecular mechanisms are not well understood. In this study, utilizing human pulmonary LAM specimens and cell culture models of TSC2-deficient LAM patient-derived and rat uterine leiomyoma-derived cells, we tested the hypothesis that estrogen promotes the growth of mTORC1-hyperactive cells through pyruvate kinase M2 (PKM2). Estrogen increased the phosphorylation of PKM2 at Ser37 and induced the nuclear translocation of phospho-PKM2. The estrogen receptor antagonist Faslodex reversed these effects. Restoration of TSC2 inhibited the phosphorylation of PKM2 in an mTORC1 inhibitor-insensitive manner. Finally, accumulation of phosphorylated PKM2 was evident in pulmonary nodule from LAM patients. Together, our data suggest that female predominance of LAM might be at least in part attributed to estrogen stimulation of PKM2-mediated cellular metabolic alterations. Targeting metabolic regulators of PKM2 might have therapeutic benefits for women with LAM and other female-specific neoplasms.</p>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosone</journal-id>
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<issn pub-type="epub">1932-6203</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, CA USA</publisher-loc>
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<article-meta><article-id pub-id-type="pmid">32078667</article-id>
<article-id pub-id-type="pmc">7032738</article-id>
<article-id pub-id-type="doi">10.1371/journal.pone.0228894</article-id>
<article-id pub-id-type="publisher-id">PONE-D-19-25163</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
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<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Hormones</subject>
<subj-group><subject>Estrogens</subject>
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<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Proteins</subject>
<subj-group><subject>Post-Translational Modification</subject>
<subj-group><subject>Phosphorylation</subject>
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<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Molecular Biology</subject>
<subj-group><subject>Molecular Biology Techniques</subject>
<subj-group><subject>Molecular Probe Techniques</subject>
<subj-group><subject>Immunoblot Analysis</subject>
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</subj-group>
</subj-group>
</subj-group>
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<subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject>
<subj-group><subject>Molecular Biology Techniques</subject>
<subj-group><subject>Molecular Probe Techniques</subject>
<subj-group><subject>Immunoblot Analysis</subject>
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</subj-group>
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</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Metabolism</subject>
<subj-group><subject>Carbohydrate Metabolism</subject>
<subj-group><subject>Glucose Metabolism</subject>
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</subj-group>
</subj-group>
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<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Oncology</subject>
<subj-group><subject>Cancers and Neoplasms</subject>
<subj-group><subject>Carcinomas</subject>
<subj-group><subject>Adenocarcinomas</subject>
<subj-group><subject>Adenocarcinoma of the Lung</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Oncology</subject>
<subj-group><subject>Cancers and Neoplasms</subject>
<subj-group><subject>Lung and Intrathoracic Tumors</subject>
<subj-group><subject>Adenocarcinoma of the Lung</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Genetics</subject>
<subj-group><subject>Gene Expression</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Cell Biology</subject>
<subj-group><subject>Cell Processes</subject>
<subj-group><subject>Cell Growth</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Metabolism</subject>
<subj-group><subject>Metabolic Processes</subject>
<subj-group><subject>Glycolysis</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Estrogen activates pyruvate kinase M2 and increases the growth of TSC2-deficient cells</article-title>
<alt-title alt-title-type="running-head">Role of PKM2 in the growth of mTORC1 hyperactive cells</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Lu</surname>
<given-names>Yiyang</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Software</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Liu</surname>
<given-names>Xiaolei</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Funding acquisition</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Project administration</role>
<role content-type="http://credit.casrai.org/">Software</role>
<role content-type="http://credit.casrai.org/">Validation</role>
<role content-type="http://credit.casrai.org/">Visualization</role>
<role content-type="http://credit.casrai.org/">Writing – original draft</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Erik</given-names>
</name>
<role content-type="http://credit.casrai.org/">Investigation</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-5429-2609</contrib-id>
<name><surname>Kopras</surname>
<given-names>Elizabeth J.</given-names>
</name>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Smith</surname>
<given-names>Eric P.</given-names>
</name>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Astreinidis</surname>
<given-names>Aristotelis</given-names>
</name>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Li</surname>
<given-names>Chenggang</given-names>
</name>
<role content-type="http://credit.casrai.org/">Investigation</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-2063-277X</contrib-id>
<name><surname>Leung</surname>
<given-names>Yuet-Kin</given-names>
</name>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff004"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ho</surname>
<given-names>Shuk-Mei</given-names>
</name>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff004"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yu</surname>
<given-names>Jane J.</given-names>
</name>
<role content-type="http://credit.casrai.org/">Conceptualization</role>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Funding acquisition</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Project administration</role>
<role content-type="http://credit.casrai.org/">Resources</role>
<role content-type="http://credit.casrai.org/">Supervision</role>
<role content-type="http://credit.casrai.org/">Validation</role>
<role content-type="http://credit.casrai.org/">Visualization</role>
<role content-type="http://credit.casrai.org/">Writing – original draft</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
</contrib-group>
<aff id="aff001"><label>1</label>
<addr-line>University of Cincinnati College of Medicine, Department of Internal Medicine, Cincinnati, OH, United States of America</addr-line>
</aff>
<aff id="aff002"><label>2</label>
<addr-line>Division of Pediatric Nephrology, Department of Pediatrics, College of Medicine, University of Tennessee Health Sciences Center and Tuberous Sclerosis Complex Center of Excellence, Le Bonheur Children’s Hospital, Memphis, TN, United States of America</addr-line>
</aff>
<aff id="aff003"><label>3</label>
<addr-line>State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China</addr-line>
</aff>
<aff id="aff004"><label>4</label>
<addr-line>College of Medicine Department of Pharmacology and Toxicology, the University of Arkansas for Medical Science (UAMS), Little Rock, AR, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Agoulnik</surname>
<given-names>Irina U.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>Florida International University, UNITED STATES</addr-line>
</aff>
<author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>
The authors have declared that no competing interests exist.</p>
</fn>
<corresp id="cor001">* E-mail: <email>yuj9@ucmail.uc.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="epub"><day>20</day>
<month>2</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="collection"><year>2020</year>
</pub-date>
<volume>15</volume>
<issue>2</issue>
<elocation-id>e0228894</elocation-id>
<history><date date-type="received"><day>9</day>
<month>9</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>24</day>
<month>1</month>
<year>2020</year>
</date>
</history>
<permissions><copyright-statement>© 2020 Lu et al</copyright-statement>
<copyright-year>2020</copyright-year>
<copyright-holder>Lu et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>
, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="pone.0228894.pdf"></self-uri>
<abstract><p>Lymphangioleiomyomatosis (LAM) is a devastating lung disease caused by inactivating gene mutations in either <italic>TSC1</italic>
or <italic>TSC2</italic>
that result in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). As LAM occurs predominantly in women during their reproductive age and is exacerbated by pregnancy, the female hormonal environment, and in particular estrogen, is implicated in LAM pathogenesis and progression. However, detailed underlying molecular mechanisms are not well understood. In this study, utilizing human pulmonary LAM specimens and cell culture models of TSC2-deficient LAM patient-derived and rat uterine leiomyoma-derived cells, we tested the hypothesis that estrogen promotes the growth of mTORC1-hyperactive cells through pyruvate kinase M2 (PKM2). Estrogen increased the phosphorylation of PKM2 at Ser37 and induced the nuclear translocation of phospho-PKM2. The estrogen receptor antagonist Faslodex reversed these effects. Restoration of TSC2 inhibited the phosphorylation of PKM2 in an mTORC1 inhibitor-insensitive manner. Finally, accumulation of phosphorylated PKM2 was evident in pulmonary nodule from LAM patients. Together, our data suggest that female predominance of LAM might be at least in part attributed to estrogen stimulation of PKM2-mediated cellular metabolic alterations. Targeting metabolic regulators of PKM2 might have therapeutic benefits for women with LAM and other female-specific neoplasms.</p>
</abstract>
<funding-group><award-group id="award001"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000002</institution-id>
<institution>National Institutes of Health</institution>
</institution-wrap>
</funding-source>
<award-id>BX000675</award-id>
<principal-award-recipient><name><surname>Ho</surname>
<given-names>Shuk-Mei</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award002"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000002</institution-id>
<institution>National Institutes of Health</institution>
</institution-wrap>
</funding-source>
<award-id>ES006096</award-id>
<principal-award-recipient><name><surname>Ho</surname>
<given-names>Shuk-Mei</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award003"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000050</institution-id>
<institution>National Heart, Lung, and Blood Institute</institution>
</institution-wrap>
</funding-source>
<award-id>RO1HL138481</award-id>
<principal-award-recipient><name><surname>Yu</surname>
<given-names>Jane J.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award004"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000050</institution-id>
<institution>National Heart, Lung, and Blood Institute</institution>
</institution-wrap>
</funding-source>
<award-id>HL098216</award-id>
<principal-award-recipient><name><surname>Yu</surname>
<given-names>Jane J.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award005"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100005963</institution-id>
<institution>LAM Foundation</institution>
</institution-wrap>
</funding-source>
<award-id>AM0140C06-19</award-id>
<principal-award-recipient><name><surname>Liu</surname>
<given-names>Xiaolei</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award006"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000062</institution-id>
<institution>National Institute of Diabetes and Digestive and Kidney Diseases</institution>
</institution-wrap>
</funding-source>
<award-id>DK098331</award-id>
<principal-award-recipient><name><surname>Yu</surname>
<given-names>Jane J.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award007"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100005963</institution-id>
<institution>LAM Foundation</institution>
</institution-wrap>
</funding-source>
<award-id>0124B07-17</award-id>
<principal-award-recipient><name><surname>Yu</surname>
<given-names>Jane J.</given-names>
</name>
</principal-award-recipient>
</award-group>
<funding-statement>The LAM Foundation Career Development Fund AM0140C06-19 to XL; CL was a LAM Foundation Fellow; BX000675 and ES006096 to SMH; RO1HL138481, HL098216, DK098331, and The LAM Foundation Bridge Fund 0124B07-17 to JJY. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><fig-count count="7"></fig-count>
<table-count count="0"></table-count>
<page-count count="20"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>All relevant data are within the paper and its Supporting Information files.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>All relevant data are within the paper and its Supporting Information files.</p>
</notes>
</front>
</pmc>
<affiliations><list><country><li>République populaire de Chine</li>
<li>États-Unis</li>
</country>
<settlement><li>Tianjin</li>
</settlement>
</list>
<tree><country name="États-Unis"><noRegion><name sortKey="Lu, Yiyang" sort="Lu, Yiyang" uniqKey="Lu Y" first="Yiyang" last="Lu">Yiyang Lu</name>
</noRegion>
<name sortKey="Astreinidis, Aristotelis" sort="Astreinidis, Aristotelis" uniqKey="Astreinidis A" first="Aristotelis" last="Astreinidis">Aristotelis Astreinidis</name>
<name sortKey="Ho, Shuk Mei" sort="Ho, Shuk Mei" uniqKey="Ho S" first="Shuk-Mei" last="Ho">Shuk-Mei Ho</name>
<name sortKey="Kopras, Elizabeth J" sort="Kopras, Elizabeth J" uniqKey="Kopras E" first="Elizabeth J." last="Kopras">Elizabeth J. Kopras</name>
<name sortKey="Leung, Yuet Kin" sort="Leung, Yuet Kin" uniqKey="Leung Y" first="Yuet-Kin" last="Leung">Yuet-Kin Leung</name>
<name sortKey="Li, Chenggang" sort="Li, Chenggang" uniqKey="Li C" first="Chenggang" last="Li">Chenggang Li</name>
<name sortKey="Liu, Xiaolei" sort="Liu, Xiaolei" uniqKey="Liu X" first="Xiaolei" last="Liu">Xiaolei Liu</name>
<name sortKey="Smith, Eric P" sort="Smith, Eric P" uniqKey="Smith E" first="Eric P." last="Smith">Eric P. Smith</name>
<name sortKey="Yu, Jane J" sort="Yu, Jane J" uniqKey="Yu J" first="Jane J." last="Yu">Jane J. Yu</name>
<name sortKey="Zhang, Erik" sort="Zhang, Erik" uniqKey="Zhang E" first="Erik" last="Zhang">Erik Zhang</name>
</country>
<country name="République populaire de Chine"><noRegion><name sortKey="Li, Chenggang" sort="Li, Chenggang" uniqKey="Li C" first="Chenggang" last="Li">Chenggang Li</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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