Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer
Identifieur interne : 000A02 ( Ncbi/Merge ); précédent : 000A01; suivant : 000A03Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer
Auteurs : Ha Gyeong Kim ; Chan Woo Kim ; Don Haeng Lee [Corée du Sud] ; Jae-Seon Lee [Corée du Sud] ; Eun-Taex Oh [Corée du Sud] ; Heon Joo Park [Corée du Sud]Source :
- International Journal of Molecular Sciences [ 1422-0067 ] ; 2019.
Abstract
5-Fluorouracil (5-FU) is an important chemotherapeutic agent for the systemic treatment of colorectal cancer (CRC), but its effectiveness against CRC is limited by increased 5-FU resistance caused by the hypoxic tumor microenvironment. The purpose of our study was to assess the feasibility of using quinacrine (QC) to increase the efficacy of 5-FU against CRC cells under hypoxic conditions. QC reversed the resistance to 5-FU induced by hypoxia in CRC cell lines, as determined using ATP-Glo cell viability assays and clonogenic survival assays. Treatment of cells with 5-FU under hypoxic conditions had no effect on the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a regulator of cellular resistance to oxidative stress, whereas treatment with QC alone or in combination with 5-FU reduced Nrf2 expression in all CRC cell lines tested. Overexpression of Nrf2 effectively prevented the increase in the number of DNA double-strand breaks induced by QC alone or in combination with 5-FU. siRNA-mediated c-Jun
Url:
DOI: 10.3390/ijms20184366
PubMed: 31491980
PubMed Central: 6770959
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<front><div type="abstract" xml:lang="en"><p>5-Fluorouracil (5-FU) is an important chemotherapeutic agent for the systemic treatment of colorectal cancer (CRC), but its effectiveness against CRC is limited by increased 5-FU resistance caused by the hypoxic tumor microenvironment. The purpose of our study was to assess the feasibility of using quinacrine (QC) to increase the efficacy of 5-FU against CRC cells under hypoxic conditions. QC reversed the resistance to 5-FU induced by hypoxia in CRC cell lines, as determined using ATP-Glo cell viability assays and clonogenic survival assays. Treatment of cells with 5-FU under hypoxic conditions had no effect on the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a regulator of cellular resistance to oxidative stress, whereas treatment with QC alone or in combination with 5-FU reduced Nrf2 expression in all CRC cell lines tested. Overexpression of Nrf2 effectively prevented the increase in the number of DNA double-strand breaks induced by QC alone or in combination with 5-FU. siRNA-mediated c-Jun <italic>N</italic>
-terminal kinase-1 (JNK1) knockdown inhibited the QC-mediated Nrf2 degradation in CRC cells under hypoxic conditions. The treatment of CRC xenografts in mice with the combination of QC and 5-FU was more effective in suppressing tumor growth than QC or 5-FU alone. QC increases the susceptibility of CRC cells to 5-FU under hypoxic conditions by enhancing JNK1-dependent Nrf2 degradation.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Mol Sci</journal-id>
<journal-id journal-id-type="iso-abbrev">Int J Mol Sci</journal-id>
<journal-id journal-id-type="publisher-id">ijms</journal-id>
<journal-title-group><journal-title>International Journal of Molecular Sciences</journal-title>
</journal-title-group>
<issn pub-type="epub">1422-0067</issn>
<publisher><publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31491980</article-id>
<article-id pub-id-type="pmc">6770959</article-id>
<article-id pub-id-type="doi">10.3390/ijms20184366</article-id>
<article-id pub-id-type="publisher-id">ijms-20-04366</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Ha Gyeong</given-names>
</name>
<xref ref-type="aff" rid="af1-ijms-20-04366">1</xref>
<xref ref-type="author-notes" rid="fn1-ijms-20-04366">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Chan Woo</given-names>
</name>
<xref ref-type="aff" rid="af1-ijms-20-04366">1</xref>
<xref ref-type="author-notes" rid="fn1-ijms-20-04366">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lee</surname>
<given-names>Don Haeng</given-names>
</name>
<xref ref-type="aff" rid="af2-ijms-20-04366">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lee</surname>
<given-names>Jae-Seon</given-names>
</name>
<xref ref-type="aff" rid="af3-ijms-20-04366">3</xref>
<xref ref-type="aff" rid="af4-ijms-20-04366">4</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-8486-3748</contrib-id>
<name><surname>Oh</surname>
<given-names>Eun-Taex</given-names>
</name>
<xref ref-type="aff" rid="af4-ijms-20-04366">4</xref>
<xref ref-type="aff" rid="af5-ijms-20-04366">5</xref>
<xref rid="c1-ijms-20-04366" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Park</surname>
<given-names>Heon Joo</given-names>
</name>
<xref ref-type="aff" rid="af1-ijms-20-04366">1</xref>
<xref ref-type="aff" rid="af4-ijms-20-04366">4</xref>
<xref rid="c1-ijms-20-04366" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="af1-ijms-20-04366"><label>1</label>
Department of Microbiology, College of Medicine, Inha University, Incheon 22212, Korea (H.G.K.) (C.W.K.)</aff>
<aff id="af2-ijms-20-04366"><label>2</label>
Department of Internal Medicine, College of Medicine, Inha University, Incheon 22212, Korea</aff>
<aff id="af3-ijms-20-04366"><label>3</label>
Department of Molecular Medicine, College of Medicine, Inha University, Incheon 22212, Korea</aff>
<aff id="af4-ijms-20-04366"><label>4</label>
Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Korea</aff>
<aff id="af5-ijms-20-04366"><label>5</label>
Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Korea</aff>
<author-notes><corresp id="c1-ijms-20-04366"><label>*</label>
Correspondence: <email>nbstoet@inha.ac.kr</email>
(E.-T.O.); <email>park001@inha.ac.kr</email>
(H.J.P.)</corresp>
<fn id="fn1-ijms-20-04366"><label>†</label>
<p>These authors contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>05</day>
<month>9</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><month>9</month>
<year>2019</year>
</pub-date>
<volume>20</volume>
<issue>18</issue>
<elocation-id>4366</elocation-id>
<history><date date-type="received"><day>17</day>
<month>7</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>04</day>
<month>9</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 by the authors.</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
).</license-p>
</license>
</permissions>
<abstract><p>5-Fluorouracil (5-FU) is an important chemotherapeutic agent for the systemic treatment of colorectal cancer (CRC), but its effectiveness against CRC is limited by increased 5-FU resistance caused by the hypoxic tumor microenvironment. The purpose of our study was to assess the feasibility of using quinacrine (QC) to increase the efficacy of 5-FU against CRC cells under hypoxic conditions. QC reversed the resistance to 5-FU induced by hypoxia in CRC cell lines, as determined using ATP-Glo cell viability assays and clonogenic survival assays. Treatment of cells with 5-FU under hypoxic conditions had no effect on the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a regulator of cellular resistance to oxidative stress, whereas treatment with QC alone or in combination with 5-FU reduced Nrf2 expression in all CRC cell lines tested. Overexpression of Nrf2 effectively prevented the increase in the number of DNA double-strand breaks induced by QC alone or in combination with 5-FU. siRNA-mediated c-Jun <italic>N</italic>
-terminal kinase-1 (JNK1) knockdown inhibited the QC-mediated Nrf2 degradation in CRC cells under hypoxic conditions. The treatment of CRC xenografts in mice with the combination of QC and 5-FU was more effective in suppressing tumor growth than QC or 5-FU alone. QC increases the susceptibility of CRC cells to 5-FU under hypoxic conditions by enhancing JNK1-dependent Nrf2 degradation.</p>
</abstract>
<kwd-group><kwd>quinacrine</kwd>
<kwd>5-flourouracil</kwd>
<kwd>hypoxia</kwd>
<kwd>Nrf2</kwd>
<kwd>colorectal cancer</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="ijms-20-04366-f001" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Quinacrine (QC) sensitizes colorectal cancer (CRC) cells to 5-fluorouracil (5-FU) treatment under hypoxic conditions. (<bold>A</bold>
) ATP-Glo assay of the QC or 5-FU treatments in HCT116, HT29, DLD1, RKO, SW620, and Colo205 cells. (<bold>B</bold>
) Summary of IC<sub>50</sub>
values and associated 95% confidence intervals (CI) for QC, 5-FU, and combined QC and 5-FU treatment in all tested CRC cell lines. (<bold>C</bold>
) Clonogenic survival assay for the QC/5-FU combination and single-agent treatments in HCT116, HT29, DLD1, RKO, SW620, and Colo205 cells. Data are presented as means ± SD (* <italic>p</italic>
< 0.05, ** <italic>p</italic>
< 0.01, *** <italic>p</italic>
< 0.001, **** <italic>p</italic>
< 0.0001 by ANOVA). “NS” indicates not significant (<italic>p</italic>
> 0.05).</p>
</caption>
<graphic xlink:href="ijms-20-04366-g001"></graphic>
</fig>
<fig id="ijms-20-04366-f002" orientation="portrait" position="float"><label>Figure 2</label>
<caption><p>QC sensitizes CRC cells to 5-FU in hypoxia by inhibiting nuclear factor (erythroid-derived 2)-like 2 (Nrf2). (<bold>A</bold>
) Scheme of the treatment and sampling procedure. (<bold>B,C</bold>
) Effect of the QC/5-FU combination on Nrf2 expression in HCT116 (<bold>B</bold>
) and RKO (<bold>C</bold>
) cells under hypoxic conditions. (<bold>D</bold>
) Effect of the QC/5-FU combination on Nrf2 expression in HT-29, DLD1, SW480, SW620, HCT15, and Colo205 cells under hypoxic conditions. Representative images of Nrf2 and β-actin were detected by immunoblot. Representative images of immunoblots for each protein were obtained using the same sample on different gels after a single experiment. (<bold>E,F</bold>
) Effect of Nrf2 overexpression on DNA damage induced in HCT116 (<bold>E</bold>
) and RKO (<bold>F</bold>
) cells by the QC/5-FU combination under hypoxic conditions. γ-H2AX (green) staining in HCT116 (<bold>E</bold>
) and RKO (<bold>F</bold>
) cells following treatment (left), and the relative percentage of foci-positive cells (right). Data are presented as means ± SD (** <italic>p</italic>
< 0.01, *** <italic>p</italic>
< 0.001, **** <italic>p</italic>
< 0.0001 by ANOVA). “NS” indicates not significant (<italic>p</italic>
> 0.05).</p>
</caption>
<graphic xlink:href="ijms-20-04366-g002"></graphic>
</fig>
<fig id="ijms-20-04366-f003" orientation="portrait" position="float"><label>Figure 3</label>
<caption><p>QC decreases Nrf2 protein stability in CRC cells. (<bold>A,B</bold>
) Effects of QC on <italic>Nrf2</italic>
mRNA expression (<bold>A</bold>
) and <italic>Nrf2</italic>
mRNA stability (<bold>B</bold>
) in HCT116 cells (left) and RKO cells (right). (<bold>C,D</bold>
) Effect of QC on Nrf2 protein stability in HCT116 cells (<bold>C</bold>
) and RKO cells (<bold>D</bold>
) under hypoxic conditions. Nrf2 protein levels were quantified using Image J software; band intensities were normalized to those of β-actin (band intensity at t<sub>0</sub>
was defined as 100%). Representative images of Nrf2 and β-actin were detected by immunoblot. Representative images of immunoblots for each protein were obtained using the same sample on different gels after a single experiment.</p>
</caption>
<graphic xlink:href="ijms-20-04366-g003"></graphic>
</fig>
<fig id="ijms-20-04366-f004" orientation="portrait" position="float"><label>Figure 4</label>
<caption><p>JNK1 activation is required for the QC-induced degradation of Nrf2 protein. (<bold>A,B</bold>
) Effect of QC on the expression of Nrf2, Keap1, Cul3, p-p38, p38, pERK1/2 (phospho extracellular signal-regulated kinases), ERK1/2, p-JNK, JNK, and β-actin in HCT116 cells (<bold>A</bold>
) and RKO cells (<bold>B</bold>
) under normoxic and hypoxic conditions. (<bold>C,D</bold>
) Effect of QC on the proteasome-mediated degradation of Nrf2 in HCT116 cells (<bold>C</bold>
) and RKO cells (<bold>D</bold>
) under normoxic and hypoxic conditions. (<bold>E,F</bold>
) Effect of QC on Keap1/Cul3-dependent degradation of Nrf2 in HCT116 cells (<bold>E</bold>
) and RKO cells (<bold>F</bold>
) under normoxic and hypoxic conditions. (<bold>G,H</bold>
) Effect of JNK1 activation on QC-induced inhibition of Nrf2 in HCT116 cells (<bold>G</bold>
) and RKO cells (<bold>H</bold>
) under normoxic and hypoxic conditions. (<bold>I,J</bold>
) Effect of QC on the interaction between Nrf2 and Keap1 in HCT116 cells (<bold>I</bold>
) and RKO cells (<bold>J</bold>
) under hypoxic conditions. Representative images of Nrf2, Keap1, Cul3, p-p38, p38, pERK1/2, ERK1/2, pJNK, JNK, and β-actin were detected by immunoblot. Representative images of immunoblots for each protein were obtained using the same sample on different gels after a single experiment.</p>
</caption>
<graphic xlink:href="ijms-20-04366-g004"></graphic>
</fig>
<fig id="ijms-20-04366-f005" orientation="portrait" position="float"><label>Figure 5</label>
<caption><p>The QC/5-FU combination inhibits tumor growth in a tumor xenograft mouse model. (<bold>A</bold>
) Tumor volume was measured at the indicated times (left panel), and tumor weight was quantified at the end of the experiment (right panel). Data are presented as means ± SEM (<italic>n</italic>
= 7 mice/group; * <italic>p</italic>
< 0.05). (<bold>B</bold>
) Representative images of immunohistochemical analyses of Nrf2 in tumors derived from HCT116 xenografts. Scale bar = 50 μm. (<bold>C</bold>
) Apoptotic cells were detected in HCT116 xenograft tumors using a TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay kit. Scale bar = 100 μm. Blue, nuclei; green, TUNEL staining. (<bold>D</bold>
) Schematic model showing how QC reverses hypoxia-induced 5-FU resistance in CRC cells under normoxia and hypoxia by inhibiting Nrf2.</p>
</caption>
<graphic xlink:href="ijms-20-04366-g005"></graphic>
</fig>
</floats-group>
</pmc>
<affiliations><list><country><li>Corée du Sud</li>
</country>
</list>
<tree><noCountry><name sortKey="Kim, Chan Woo" sort="Kim, Chan Woo" uniqKey="Kim C" first="Chan Woo" last="Kim">Chan Woo Kim</name>
<name sortKey="Kim, Ha Gyeong" sort="Kim, Ha Gyeong" uniqKey="Kim H" first="Ha Gyeong" last="Kim">Ha Gyeong Kim</name>
</noCountry>
<country name="Corée du Sud"><noRegion><name sortKey="Lee, Don Haeng" sort="Lee, Don Haeng" uniqKey="Lee D" first="Don Haeng" last="Lee">Don Haeng Lee</name>
</noRegion>
<name sortKey="Lee, Jae Seon" sort="Lee, Jae Seon" uniqKey="Lee J" first="Jae-Seon" last="Lee">Jae-Seon Lee</name>
<name sortKey="Lee, Jae Seon" sort="Lee, Jae Seon" uniqKey="Lee J" first="Jae-Seon" last="Lee">Jae-Seon Lee</name>
<name sortKey="Oh, Eun Taex" sort="Oh, Eun Taex" uniqKey="Oh E" first="Eun-Taex" last="Oh">Eun-Taex Oh</name>
<name sortKey="Oh, Eun Taex" sort="Oh, Eun Taex" uniqKey="Oh E" first="Eun-Taex" last="Oh">Eun-Taex Oh</name>
<name sortKey="Park, Heon Joo" sort="Park, Heon Joo" uniqKey="Park H" first="Heon Joo" last="Park">Heon Joo Park</name>
</country>
</tree>
</affiliations>
</record>
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