Impairment of HIF-1α-mediated metabolic adaption by NRF2-silencing in breast cancer cells
Identifieur interne : 000611 ( Ncbi/Merge ); précédent : 000610; suivant : 000612Impairment of HIF-1α-mediated metabolic adaption by NRF2-silencing in breast cancer cells
Auteurs : Sujin Lee [Corée du Sud] ; Steffanus Pranoto Hallis [Corée du Sud, Indonésie] ; Kyeong-Ah Jung [Corée du Sud] ; Dayoung Ryu [Corée du Sud] ; Mi-Kyoung Kwak [Corée du Sud]Source :
- Redox Biology [ 2213-2317 ] ; 2019.
Abstract
Hypoxia, a common element in the tumor environment, leads to Hypoxia-Inducible Factor-1α (HIF-1α) stabilization to modulate cellular metabolism as an adaptive response. In a previous study, we showed that inhibition of the nuclear factor erythroid 2-like-2 (NFE2L2; NRF2), a master regulator of many genes coping with electrophilic and oxidative stress, elevated the level of
Url:
DOI: 10.1016/j.redox.2019.101210
PubMed: 31078780
PubMed Central: 6514540
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<front><div type="abstract" xml:lang="en"><p>Hypoxia, a common element in the tumor environment, leads to Hypoxia-Inducible Factor-1α (HIF-1α) stabilization to modulate cellular metabolism as an adaptive response. In a previous study, we showed that inhibition of the nuclear factor erythroid 2-like-2 (NFE2L2; NRF2), a master regulator of many genes coping with electrophilic and oxidative stress, elevated the level of <italic>miR-181c</italic>
and induced mitochondrial dysfunction in colon cancer cells. In this study, we demonstrate that <italic>NRF2</italic>
-silencing hindered HIF-1α accumulation in hypoxic breast cancer cells and subsequently suppressed hypoxia-inducible expression of glycolysis-associated glucose transporter-1, hexokinase-2, pyruvate dehydrogenase kinase-1, and lactate dehydrogenase A. HIF-1α dysregulation in <italic>NRF2</italic>
-silenced cancer cells was associated with <italic>miR-181c</italic>
elevation. Overexpression of <italic>miR-181c</italic>
in breast cancer cells blocked HIF-1α accumulation and diminished hypoxia-inducible levels of glycolysis enzymes, whereas the inhibition of <italic>miR-181c</italic>
in <italic>NRF2</italic>
-silenced cells restored HIF-1α accumulation. In a subsequent metabolomic analysis, hypoxic incubation increased the levels of metabolites involved in glycolysis and activated the pentose phosphate pathway (PPP) in control cells. However, these elevations were less pronounced in <italic>NRF2</italic>
-silenced cells. In particular, hypoxic incubation increased the levels of amino acids, which implies a shift to catabolic metabolism, and the increased levels were higher in control cells than in <italic>NRF2</italic>
-silenced cells. Concurrently, hypoxia activated BCL2 interacting protein 3 (BNIP3)-mediated autophagy in the control cells and <italic>miR-181c</italic>
was found to be involved in this autophagy activation. Taken together, these results show that hypoxia-induced metabolic changes to glycolysis, the PPP, and autophagy are inhibited by <italic>NRF2</italic>
-silencing through <italic>miR-181c</italic>
-mediated HIF-1α dysregulation. Therefore, targeting <italic>NRF2</italic>
/<italic>miR-181c</italic>
could be an effective strategy to counteract HIF-1α-orchestrated metabolic adaptation of hypoxic cancer cells.</p>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Redox Biol</journal-id>
<journal-id journal-id-type="iso-abbrev">Redox Biol</journal-id>
<journal-title-group><journal-title>Redox Biology</journal-title>
</journal-title-group>
<issn pub-type="epub">2213-2317</issn>
<publisher><publisher-name>Elsevier</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31078780</article-id>
<article-id pub-id-type="pmc">6514540</article-id>
<article-id pub-id-type="publisher-id">S2213-2317(19)30050-3</article-id>
<article-id pub-id-type="doi">10.1016/j.redox.2019.101210</article-id>
<article-id pub-id-type="publisher-id">101210</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject>
</subj-group>
</article-categories>
<title-group><article-title>Impairment of HIF-1α-mediated metabolic adaption by <italic>NRF2</italic>
-silencing in breast cancer cells</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Lee</surname>
<given-names>Sujin</given-names>
</name>
<xref rid="aff1" ref-type="aff">a</xref>
<xref rid="fn1" ref-type="fn">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hallis</surname>
<given-names>Steffanus Pranoto</given-names>
</name>
<xref rid="aff1" ref-type="aff">a</xref>
<xref rid="aff2" ref-type="aff">b</xref>
<xref rid="fn1" ref-type="fn">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jung</surname>
<given-names>Kyeong-Ah</given-names>
</name>
<xref rid="aff3" ref-type="aff">c</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ryu</surname>
<given-names>Dayoung</given-names>
</name>
<xref rid="aff1" ref-type="aff">a</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kwak</surname>
<given-names>Mi-Kyoung</given-names>
</name>
<email>mkwak@catholic.ac.kr</email>
<xref rid="aff1" ref-type="aff">a</xref>
<xref rid="aff3" ref-type="aff">c</xref>
<xref rid="aff4" ref-type="aff">d</xref>
<xref rid="cor1" ref-type="corresp">∗</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>a</label>
Department of Pharmacy and BK21PLUS Team for Creative Leader Program for Pharmacomics-based Future Pharmacy, Graduate School of The Catholic University of Korea, 43 Jibong-ro, Bucheon, Gyeonggi-do, 14662, Republic of Korea</aff>
<aff id="aff2"><label>b</label>
Faculty of Biotechnology, Atma Jaya Catholic University of Indonesia, Jakarta, 12930, Indonesia</aff>
<aff id="aff3"><label>c</label>
Integrated Research Institute for Pharmaceutical Sciences, The Catholic University of Korea, Republic of Korea</aff>
<aff id="aff4"><label>d</label>
College of Pharmacy, The Catholic University of Korea, Republic of Korea</aff>
<author-notes><corresp id="cor1"><label>∗</label>
Corresponding author. College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Bucheon, Gyeonggi-do, 14662, Republic of Korea. <email>mkwak@catholic.ac.kr</email>
</corresp>
<fn id="fn1"><label>1</label>
<p id="ntpara0010">S. Lee and S. P. Hallis contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="pmc-release"><day>02</day>
<month>5</month>
<year>2019</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="collection"><month>6</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="epub"><day>02</day>
<month>5</month>
<year>2019</year>
</pub-date>
<volume>24</volume>
<elocation-id>101210</elocation-id>
<history><date date-type="received"><day>9</day>
<month>1</month>
<year>2019</year>
</date>
<date date-type="rev-recd"><day>4</day>
<month>4</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>27</day>
<month>4</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 The Authors</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="CC BY" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</license-p>
</license>
</permissions>
<abstract id="abs0010"><p>Hypoxia, a common element in the tumor environment, leads to Hypoxia-Inducible Factor-1α (HIF-1α) stabilization to modulate cellular metabolism as an adaptive response. In a previous study, we showed that inhibition of the nuclear factor erythroid 2-like-2 (NFE2L2; NRF2), a master regulator of many genes coping with electrophilic and oxidative stress, elevated the level of <italic>miR-181c</italic>
and induced mitochondrial dysfunction in colon cancer cells. In this study, we demonstrate that <italic>NRF2</italic>
-silencing hindered HIF-1α accumulation in hypoxic breast cancer cells and subsequently suppressed hypoxia-inducible expression of glycolysis-associated glucose transporter-1, hexokinase-2, pyruvate dehydrogenase kinase-1, and lactate dehydrogenase A. HIF-1α dysregulation in <italic>NRF2</italic>
-silenced cancer cells was associated with <italic>miR-181c</italic>
elevation. Overexpression of <italic>miR-181c</italic>
in breast cancer cells blocked HIF-1α accumulation and diminished hypoxia-inducible levels of glycolysis enzymes, whereas the inhibition of <italic>miR-181c</italic>
in <italic>NRF2</italic>
-silenced cells restored HIF-1α accumulation. In a subsequent metabolomic analysis, hypoxic incubation increased the levels of metabolites involved in glycolysis and activated the pentose phosphate pathway (PPP) in control cells. However, these elevations were less pronounced in <italic>NRF2</italic>
-silenced cells. In particular, hypoxic incubation increased the levels of amino acids, which implies a shift to catabolic metabolism, and the increased levels were higher in control cells than in <italic>NRF2</italic>
-silenced cells. Concurrently, hypoxia activated BCL2 interacting protein 3 (BNIP3)-mediated autophagy in the control cells and <italic>miR-181c</italic>
was found to be involved in this autophagy activation. Taken together, these results show that hypoxia-induced metabolic changes to glycolysis, the PPP, and autophagy are inhibited by <italic>NRF2</italic>
-silencing through <italic>miR-181c</italic>
-mediated HIF-1α dysregulation. Therefore, targeting <italic>NRF2</italic>
/<italic>miR-181c</italic>
could be an effective strategy to counteract HIF-1α-orchestrated metabolic adaptation of hypoxic cancer cells.</p>
</abstract>
<abstract abstract-type="graphical" id="abs0015"><title>Graphical abstract</title>
<p><fig id="undfig1" position="anchor"><alt-text id="alttext0010">Image 1</alt-text>
<graphic xlink:href="fx1"></graphic>
</fig>
</p>
</abstract>
<kwd-group id="kwrds0010"><title>Keywords</title>
<kwd>Hypoxia</kwd>
<kwd>Metabolism</kwd>
<kwd>Autophagy</kwd>
<kwd>HIF-1α</kwd>
<kwd>NFE2L2/NRF2</kwd>
<kwd>Metabolome</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Corée du Sud</li>
<li>Indonésie</li>
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<name sortKey="Kwak, Mi Kyoung" sort="Kwak, Mi Kyoung" uniqKey="Kwak M" first="Mi-Kyoung" last="Kwak">Mi-Kyoung Kwak</name>
<name sortKey="Kwak, Mi Kyoung" sort="Kwak, Mi Kyoung" uniqKey="Kwak M" first="Mi-Kyoung" last="Kwak">Mi-Kyoung Kwak</name>
<name sortKey="Ryu, Dayoung" sort="Ryu, Dayoung" uniqKey="Ryu D" first="Dayoung" last="Ryu">Dayoung Ryu</name>
</country>
<country name="Indonésie"><noRegion><name sortKey="Hallis, Steffanus Pranoto" sort="Hallis, Steffanus Pranoto" uniqKey="Hallis S" first="Steffanus Pranoto" last="Hallis">Steffanus Pranoto Hallis</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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