MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling
Identifieur interne : 000907 ( Ncbi/Merge ); précédent : 000906; suivant : 000908MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling
Auteurs : Ping Jin [République populaire de Chine] ; Jingwen Jiang [République populaire de Chine] ; Na Xie [République populaire de Chine] ; Li Zhou [République populaire de Chine] ; Zhao Huang [République populaire de Chine] ; Lu Zhang [République populaire de Chine] ; Siyuan Qin [République populaire de Chine] ; Shuyue Fu [République populaire de Chine] ; Liyuan Peng [République populaire de Chine] ; Wei Gao [République populaire de Chine] ; Bowen Li [République populaire de Chine] ; Yunlong Lei [République populaire de Chine] ; Edouard C. Nice ; Changlong Li [République populaire de Chine] ; Jichun Shao ; Ke XieSource :
- Cell Death & Disease [ 2041-4889 ] ; 2019.
Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Development of novel chemotherapeutics is still required to enable successful treatment and improve survival for CRC patients. Here, we found that osimertinib (OSI) exhibits potent anti-CRC effects by inducing apoptosis, independent of its selective inhibitory activity targeting the EGFR T790M mutation. Intriguingly, OSI treatment triggers autophagic flux in CRC cells. Inhibition of autophagy markedly augments OSI-induced apoptosis and growth inhibition in CRC cells, suggesting a protective role of autophagy in response to OSI treatment. Mechanistically, OSI upregulates the expression of monocarboxylate transporter 1 (MCT1) and subsequently activates LKB1/AMPK signaling, leading to autophagy induction in CRC cells. Notably, OSI significantly exaggerates the sensitivity of CRC cells to the first-line drugs 5-fluorouracil or oxaliplatin. Taken together, our study unravels a novel mechanism of OSI-mediated protective autophagy involving MCT1/LKB1/AMPK signaling, and suggests the use of OSI as a potential agent for clinical CRC treatment.
Url:
DOI: 10.1038/s41419-019-1844-2
PubMed: 31409796
PubMed Central: 6692318
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<institution>Sichuan University, and Collaborative Innovation Center for Biotherapy,</institution>
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Chengdu, 610041 P. R. China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Chengdu</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lei, Yunlong" sort="Lei, Yunlong" uniqKey="Lei Y" first="Yunlong" last="Lei">Yunlong Lei</name>
<affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8653 0555</institution-id>
<institution-id institution-id-type="GRID">grid.203458.8</institution-id>
<institution>Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center,</institution>
<institution>Chongqing Medical University,</institution>
</institution-wrap>
Chongqing, 400016 P. R. China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Chongqing</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nice, Edouard C" sort="Nice, Edouard C" uniqKey="Nice E" first="Edouard C." last="Nice">Edouard C. Nice</name>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 7857</institution-id>
<institution-id institution-id-type="GRID">grid.1002.3</institution-id>
<institution>Department of Biochemistry and Molecular Biology,</institution>
<institution>Monash University,</institution>
</institution-wrap>
Clayton, VIC 3800 Australia</nlm:aff>
<wicri:noCountry code="subfield">VIC 3800 Australia</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Li, Changlong" sort="Li, Changlong" uniqKey="Li C" first="Changlong" last="Li">Changlong Li</name>
<affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0807 1581</institution-id>
<institution-id institution-id-type="GRID">grid.13291.38</institution-id>
<institution>West China School of Basic Medical Sciences & Forensic Medicine,</institution>
<institution>Sichuan University,</institution>
</institution-wrap>
Chengdu, 610041 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Chengdu</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Shao, Jichun" sort="Shao, Jichun" uniqKey="Shao J" first="Jichun" last="Shao">Jichun Shao</name>
<affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1799 3643</institution-id>
<institution-id institution-id-type="GRID">grid.413856.d</institution-id>
<institution>Department of Urology,</institution>
<institution>Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital),</institution>
</institution-wrap>
Chengdu, Sichuan China</nlm:aff>
<wicri:noCountry code="subfield">Sichuan China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Xie, Ke" sort="Xie, Ke" uniqKey="Xie K" first="Ke" last="Xie">Ke Xie</name>
<affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 4060</institution-id>
<institution-id institution-id-type="GRID">grid.54549.39</institution-id>
<institution>Department of Oncology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine,</institution>
<institution>University of Electronic Science and Technology of China,</institution>
</institution-wrap>
Chengdu, Sichuan 610054 P. R. China</nlm:aff>
<wicri:noCountry code="subfield">Sichuan 610054 P. R. China</wicri:noCountry>
</affiliation>
</author>
</analytic>
<series><title level="j">Cell Death & Disease</title>
<idno type="eISSN">2041-4889</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="Par1">Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Development of novel chemotherapeutics is still required to enable successful treatment and improve survival for CRC patients. Here, we found that osimertinib (OSI) exhibits potent anti-CRC effects by inducing apoptosis, independent of its selective inhibitory activity targeting the EGFR T790M mutation. Intriguingly, OSI treatment triggers autophagic flux in CRC cells. Inhibition of autophagy markedly augments OSI-induced apoptosis and growth inhibition in CRC cells, suggesting a protective role of autophagy in response to OSI treatment. Mechanistically, OSI upregulates the expression of monocarboxylate transporter 1 (MCT1) and subsequently activates LKB1/AMPK signaling, leading to autophagy induction in CRC cells. Notably, OSI significantly exaggerates the sensitivity of CRC cells to the first-line drugs 5-fluorouracil or oxaliplatin. Taken together, our study unravels a novel mechanism of OSI-mediated protective autophagy involving MCT1/LKB1/AMPK signaling, and suggests the use of OSI as a potential agent for clinical CRC treatment.</p>
</div>
</front>
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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">Cell Death Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">Cell Death Dis</journal-id>
<journal-title-group><journal-title>Cell Death & Disease</journal-title>
</journal-title-group>
<issn pub-type="epub">2041-4889</issn>
<publisher><publisher-name>Nature Publishing Group UK</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31409796</article-id>
<article-id pub-id-type="pmc">6692318</article-id>
<article-id pub-id-type="publisher-id">1844</article-id>
<article-id pub-id-type="doi">10.1038/s41419-019-1844-2</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Jin</surname>
<given-names>Ping</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Jiang</surname>
<given-names>Jingwen</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Xie</surname>
<given-names>Na</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhou</surname>
<given-names>Li</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Huang</surname>
<given-names>Zhao</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-8325-2793</contrib-id>
<name><surname>Zhang</surname>
<given-names>Lu</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Qin</surname>
<given-names>Siyuan</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fu</surname>
<given-names>Shuyue</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Peng</surname>
<given-names>Liyuan</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gao</surname>
<given-names>Wei</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Li</surname>
<given-names>Bowen</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lei</surname>
<given-names>Yunlong</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nice</surname>
<given-names>Edouard C.</given-names>
</name>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Li</surname>
<given-names>Changlong</given-names>
</name>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Shao</surname>
<given-names>Jichun</given-names>
</name>
<address><phone>+86 13072862698</phone>
<email>shaoji93@163.com</email>
</address>
<xref ref-type="aff" rid="Aff5">5</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Xie</surname>
<given-names>Ke</given-names>
</name>
<address><phone>+86 18981838382</phone>
<email>xieke@med.uestc.edu.cn</email>
</address>
<xref ref-type="aff" rid="Aff6">6</xref>
</contrib>
<aff id="Aff1"><label>1</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0807 1581</institution-id>
<institution-id institution-id-type="GRID">grid.13291.38</institution-id>
<institution>State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine,</institution>
<institution>Sichuan University, and Collaborative Innovation Center for Biotherapy,</institution>
</institution-wrap>
Chengdu, 610041 P. R. China</aff>
<aff id="Aff2"><label>2</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8653 0555</institution-id>
<institution-id institution-id-type="GRID">grid.203458.8</institution-id>
<institution>Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center,</institution>
<institution>Chongqing Medical University,</institution>
</institution-wrap>
Chongqing, 400016 P. R. China</aff>
<aff id="Aff3"><label>3</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 7857</institution-id>
<institution-id institution-id-type="GRID">grid.1002.3</institution-id>
<institution>Department of Biochemistry and Molecular Biology,</institution>
<institution>Monash University,</institution>
</institution-wrap>
Clayton, VIC 3800 Australia</aff>
<aff id="Aff4"><label>4</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0807 1581</institution-id>
<institution-id institution-id-type="GRID">grid.13291.38</institution-id>
<institution>West China School of Basic Medical Sciences & Forensic Medicine,</institution>
<institution>Sichuan University,</institution>
</institution-wrap>
Chengdu, 610041 China</aff>
<aff id="Aff5"><label>5</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1799 3643</institution-id>
<institution-id institution-id-type="GRID">grid.413856.d</institution-id>
<institution>Department of Urology,</institution>
<institution>Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital),</institution>
</institution-wrap>
Chengdu, Sichuan China</aff>
<aff id="Aff6"><label>6</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 4060</institution-id>
<institution-id institution-id-type="GRID">grid.54549.39</institution-id>
<institution>Department of Oncology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine,</institution>
<institution>University of Electronic Science and Technology of China,</institution>
</institution-wrap>
Chengdu, Sichuan 610054 P. R. China</aff>
</contrib-group>
<pub-date pub-type="epub"><day>13</day>
<month>8</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>13</day>
<month>8</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><month>8</month>
<year>2019</year>
</pub-date>
<volume>10</volume>
<issue>8</issue>
<elocation-id>615</elocation-id>
<history><date date-type="received"><day>10</day>
<month>3</month>
<year>2019</year>
</date>
<date date-type="rev-recd"><day>21</day>
<month>7</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>24</day>
<month>7</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s) 2019</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <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 id="Abs1"><p id="Par1">Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Development of novel chemotherapeutics is still required to enable successful treatment and improve survival for CRC patients. Here, we found that osimertinib (OSI) exhibits potent anti-CRC effects by inducing apoptosis, independent of its selective inhibitory activity targeting the EGFR T790M mutation. Intriguingly, OSI treatment triggers autophagic flux in CRC cells. Inhibition of autophagy markedly augments OSI-induced apoptosis and growth inhibition in CRC cells, suggesting a protective role of autophagy in response to OSI treatment. Mechanistically, OSI upregulates the expression of monocarboxylate transporter 1 (MCT1) and subsequently activates LKB1/AMPK signaling, leading to autophagy induction in CRC cells. Notably, OSI significantly exaggerates the sensitivity of CRC cells to the first-line drugs 5-fluorouracil or oxaliplatin. Taken together, our study unravels a novel mechanism of OSI-mediated protective autophagy involving MCT1/LKB1/AMPK signaling, and suggests the use of OSI as a potential agent for clinical CRC treatment.</p>
</abstract>
<kwd-group kwd-group-type="npg-subject"><title>Subject terms</title>
<kwd>Cancer</kwd>
<kwd>Cell biology</kwd>
</kwd-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2019</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>République populaire de Chine</li>
</country>
</list>
<tree><noCountry><name sortKey="Nice, Edouard C" sort="Nice, Edouard C" uniqKey="Nice E" first="Edouard C." last="Nice">Edouard C. Nice</name>
<name sortKey="Shao, Jichun" sort="Shao, Jichun" uniqKey="Shao J" first="Jichun" last="Shao">Jichun Shao</name>
<name sortKey="Xie, Ke" sort="Xie, Ke" uniqKey="Xie K" first="Ke" last="Xie">Ke Xie</name>
</noCountry>
<country name="République populaire de Chine"><noRegion><name sortKey="Jin, Ping" sort="Jin, Ping" uniqKey="Jin P" first="Ping" last="Jin">Ping Jin</name>
</noRegion>
<name sortKey="Fu, Shuyue" sort="Fu, Shuyue" uniqKey="Fu S" first="Shuyue" last="Fu">Shuyue Fu</name>
<name sortKey="Gao, Wei" sort="Gao, Wei" uniqKey="Gao W" first="Wei" last="Gao">Wei Gao</name>
<name sortKey="Huang, Zhao" sort="Huang, Zhao" uniqKey="Huang Z" first="Zhao" last="Huang">Zhao Huang</name>
<name sortKey="Jiang, Jingwen" sort="Jiang, Jingwen" uniqKey="Jiang J" first="Jingwen" last="Jiang">Jingwen Jiang</name>
<name sortKey="Lei, Yunlong" sort="Lei, Yunlong" uniqKey="Lei Y" first="Yunlong" last="Lei">Yunlong Lei</name>
<name sortKey="Li, Bowen" sort="Li, Bowen" uniqKey="Li B" first="Bowen" last="Li">Bowen Li</name>
<name sortKey="Li, Changlong" sort="Li, Changlong" uniqKey="Li C" first="Changlong" last="Li">Changlong Li</name>
<name sortKey="Peng, Liyuan" sort="Peng, Liyuan" uniqKey="Peng L" first="Liyuan" last="Peng">Liyuan Peng</name>
<name sortKey="Qin, Siyuan" sort="Qin, Siyuan" uniqKey="Qin S" first="Siyuan" last="Qin">Siyuan Qin</name>
<name sortKey="Xie, Na" sort="Xie, Na" uniqKey="Xie N" first="Na" last="Xie">Na Xie</name>
<name sortKey="Zhang, Lu" sort="Zhang, Lu" uniqKey="Zhang L" first="Lu" last="Zhang">Lu Zhang</name>
<name sortKey="Zhou, Li" sort="Zhou, Li" uniqKey="Zhou L" first="Li" last="Zhou">Li Zhou</name>
</country>
</tree>
</affiliations>
</record>
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