The NEDD4‐1 E3 ubiquitin ligase: A potential molecular target for bortezomib sensitivity in multiple myeloma
Identifieur interne : 000598 ( Pmc/Curation ); précédent : 000597; suivant : 000599The NEDD4‐1 E3 ubiquitin ligase: A potential molecular target for bortezomib sensitivity in multiple myeloma
Auteurs : Xi Huang ; Huiyao Gu ; Enfan Zhang ; Qingxiao Chen ; Wen Cao ; Haimeng Yan ; Jing Chen ; Li Yang ; Ning Lv ; Jingsong He ; Qing Yi ; Zhen CaiSource :
- International Journal of Cancer [ 0020-7136 ] ; 2019.
Abstract
E3 ubiquitin ligases primarily determine the substrate specificity of the ubiquitin‐proteasome system and play an essential role in the resistance to bortezomib in multiple myeloma (MM). Neural precursor cell‐expressed developmentally downregulated gene 4‐1 (NEDD4‐1, also known as NEDD4) is a founding member of the NEDD4 family of E3 ligases and is involved in the proliferation, migration, invasion and drug sensitivity of cancer cells. In the present study, we investigated the role of NEDD4‐1 in MM cells and explored its underlying mechanism. Clinically, low NEDD4‐1 expression has been linked to poor prognosis in patients with MM. Functionally, NEDD4‐1 knockdown (KD) resulted in bortezomib resistance in MM cells
Url:
DOI: 10.1002/ijc.32615
PubMed: 31390487
PubMed Central: 7027789
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The NEDD4‐1 E3 ubiquitin ligase: A potential molecular target for bortezomib sensitivity in multiple myeloma</title>
<author><name sortKey="Huang, Xi" sort="Huang, Xi" uniqKey="Huang X" first="Xi" last="Huang">Xi Huang</name>
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<author><name sortKey="Zhang, Enfan" sort="Zhang, Enfan" uniqKey="Zhang E" first="Enfan" last="Zhang">Enfan Zhang</name>
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<author><name sortKey="Chen, Qingxiao" sort="Chen, Qingxiao" uniqKey="Chen Q" first="Qingxiao" last="Chen">Qingxiao Chen</name>
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<front><div type="abstract" xml:lang="en"><p>E3 ubiquitin ligases primarily determine the substrate specificity of the ubiquitin‐proteasome system and play an essential role in the resistance to bortezomib in multiple myeloma (MM). Neural precursor cell‐expressed developmentally downregulated gene 4‐1 (NEDD4‐1, also known as NEDD4) is a founding member of the NEDD4 family of E3 ligases and is involved in the proliferation, migration, invasion and drug sensitivity of cancer cells. In the present study, we investigated the role of NEDD4‐1 in MM cells and explored its underlying mechanism. Clinically, low NEDD4‐1 expression has been linked to poor prognosis in patients with MM. Functionally, NEDD4‐1 knockdown (KD) resulted in bortezomib resistance in MM cells <italic>in vitro</italic>
and <italic>in vivo</italic>
. The overexpression (OE) of NEDD4‐1, but not an enzyme‐dead NEDD4‐1‐C867S mutant, had the opposite effect. Furthermore, the overexpression of NEDD4‐1 in NEDD4‐1 KD cells resensitized the cells to bortezomib in an add‐back rescue experiment. Mechanistically, pAkt‐Ser473 levels and Akt signaling were elevated and decreased by NEDD4‐1 KD and OE, respectively. NEDD4‐1 ubiquitinated Akt and targeted pAkt‐Ser473 for proteasomal degradation. More importantly, the NEDD4‐1 KD‐induced upregulation of Akt expression sensitized MM cells to growth inhibition after treatment with an Akt inhibitor. Collectively, our results suggest that high NEDD4‐1 levels may be a potential new therapeutic target in MM.</p>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Cancer</journal-id>
<journal-id journal-id-type="iso-abbrev">Int. J. Cancer</journal-id>
<journal-id journal-id-type="doi">10.1002/(ISSN)1097-0215</journal-id>
<journal-id journal-id-type="publisher-id">IJC</journal-id>
<journal-title-group><journal-title>International Journal of Cancer</journal-title>
</journal-title-group>
<issn pub-type="ppub">0020-7136</issn>
<issn pub-type="epub">1097-0215</issn>
<publisher><publisher-name>John Wiley & Sons, Inc.</publisher-name>
<publisher-loc>Hoboken, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31390487</article-id>
<article-id pub-id-type="pmc">7027789</article-id>
<article-id pub-id-type="doi">10.1002/ijc.32615</article-id>
<article-id pub-id-type="publisher-id">IJC32615</article-id>
<article-categories><subj-group subj-group-type="overline"><subject>Molecular Cancer Biology</subject>
</subj-group>
<subj-group subj-group-type="heading"><subject>Molecular Cancer Biology</subject>
</subj-group>
</article-categories>
<title-group><article-title>The NEDD4‐1 E3 ubiquitin ligase: A potential molecular target for bortezomib sensitivity in multiple myeloma</article-title>
<alt-title alt-title-type="right-running-head">NEDD4‐1 modulates the sensitivity of myeloma to Bor</alt-title>
<alt-title alt-title-type="left-running-head">Huang <italic>et al</italic>
.</alt-title>
</title-group>
<contrib-group><contrib id="ijc32615-cr-0001" contrib-type="author"><name><surname>Huang</surname>
<given-names>Xi</given-names>
</name>
<xref ref-type="aff" rid="ijc32615-aff-0001"><sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="ijc32615-note-0001"><sup>†</sup>
</xref>
</contrib>
<contrib id="ijc32615-cr-0002" contrib-type="author"><name><surname>Gu</surname>
<given-names>Huiyao</given-names>
</name>
<xref ref-type="aff" rid="ijc32615-aff-0001"><sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="ijc32615-note-0001"><sup>†</sup>
</xref>
</contrib>
<contrib id="ijc32615-cr-0003" contrib-type="author"><name><surname>Zhang</surname>
<given-names>Enfan</given-names>
</name>
<xref ref-type="aff" rid="ijc32615-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="ijc32615-cr-0004" contrib-type="author"><name><surname>Chen</surname>
<given-names>Qingxiao</given-names>
</name>
<xref ref-type="aff" rid="ijc32615-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="ijc32615-cr-0005" contrib-type="author"><name><surname>Cao</surname>
<given-names>Wen</given-names>
</name>
<xref ref-type="aff" rid="ijc32615-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="ijc32615-cr-0006" contrib-type="author"><name><surname>Yan</surname>
<given-names>Haimeng</given-names>
</name>
<xref ref-type="aff" rid="ijc32615-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="ijc32615-cr-0007" contrib-type="author"><name><surname>Chen</surname>
<given-names>Jing</given-names>
</name>
<xref ref-type="aff" rid="ijc32615-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="ijc32615-cr-0008" contrib-type="author"><name><surname>Yang</surname>
<given-names>Li</given-names>
</name>
<xref ref-type="aff" rid="ijc32615-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="ijc32615-cr-0009" contrib-type="author"><name><surname>Lv</surname>
<given-names>Ning</given-names>
</name>
<xref ref-type="aff" rid="ijc32615-aff-0002"><sup>2</sup>
</xref>
</contrib>
<contrib id="ijc32615-cr-0010" contrib-type="author"><name><surname>He</surname>
<given-names>Jingsong</given-names>
</name>
<xref ref-type="aff" rid="ijc32615-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="ijc32615-cr-0011" contrib-type="author"><name><surname>Yi</surname>
<given-names>Qing</given-names>
</name>
<xref ref-type="aff" rid="ijc32615-aff-0003"><sup>3</sup>
</xref>
</contrib>
<contrib id="ijc32615-cr-0012" contrib-type="author" corresp="yes"><name><surname>Cai</surname>
<given-names>Zhen</given-names>
</name>
<contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-6026-3804</contrib-id>
<xref ref-type="aff" rid="ijc32615-aff-0001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="ijc32615-aff-0004"><sup>4</sup>
</xref>
<address><email>caiz@zju.edu.cn</email>
</address>
</contrib>
</contrib-group>
<aff id="ijc32615-aff-0001"><label><sup>1</sup>
</label>
<named-content content-type="organisation-division">Bone Marrow Transplantation Center, Department of Hematology</named-content>
<institution>The First Affiliated Hospital, School of Medicine, Zhejiang University</institution>
<city>Hangzhou</city>
<country country="CN">China</country>
</aff>
<aff id="ijc32615-aff-0002"><label><sup>2</sup>
</label>
<named-content content-type="organisation-division">Department of Pharmacy</named-content>
<institution>The First Affiliated Hospital, School of Medicine, Zhejiang University</institution>
<city>Hangzhou</city>
<country country="CN">China</country>
</aff>
<aff id="ijc32615-aff-0003"><label><sup>3</sup>
</label>
<institution>Center for Hematologic Malignancy Research Institute, Houston Methodist</institution>
<city>Houston</city>
<named-content content-type="country-part">TX</named-content>
</aff>
<aff id="ijc32615-aff-0004"><label><sup>4</sup>
</label>
<institution>Institute of Hematology, Zhejiang University</institution>
<city>China</city>
</aff>
<author-notes><corresp id="correspondenceTo"><label>*</label>
<bold>Correspondence to:</bold>
Zhen Cai, Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79, Qingchun Road, Hangzhou, Zhejiang Province, China, Tel.: +86‐571‐87236706, Fax: +86‐571‐87236706, E‐mail: <email>caiz@zju.edu.cn</email>
</corresp>
<fn id="ijc32615-note-0001"><label>†</label>
<p>X.H. and H.G. contributed equally to this work</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>24</day>
<month>8</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="ppub"><day>01</day>
<month>4</month>
<year>2020</year>
</pub-date>
<volume>146</volume>
<issue>7</issue>
<issue-id pub-id-type="doi">10.1002/ijc.v146.7</issue-id>
<fpage>1963</fpage>
<lpage>1978</lpage>
<history><date date-type="received"><day>05</day>
<month>3</month>
<year>2019</year>
</date>
<date date-type="rev-recd"><day>04</day>
<month>7</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>31</day>
<month>7</month>
<year>2019</year>
</date>
</history>
<permissions><pmc-comment> © 2020 UICC </pmc-comment>
<copyright-statement content-type="article-copyright">© 2019 The Authors. <italic>International Journal of Cancer</italic>
published by John Wiley & Sons Ltd on behalf of UICC</copyright-statement>
<license license-type="creativeCommonsBy"><license-p>This is an open access article under the terms of the <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, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="file:IJC-146-1963.pdf"></self-uri>
<abstract><p>E3 ubiquitin ligases primarily determine the substrate specificity of the ubiquitin‐proteasome system and play an essential role in the resistance to bortezomib in multiple myeloma (MM). Neural precursor cell‐expressed developmentally downregulated gene 4‐1 (NEDD4‐1, also known as NEDD4) is a founding member of the NEDD4 family of E3 ligases and is involved in the proliferation, migration, invasion and drug sensitivity of cancer cells. In the present study, we investigated the role of NEDD4‐1 in MM cells and explored its underlying mechanism. Clinically, low NEDD4‐1 expression has been linked to poor prognosis in patients with MM. Functionally, NEDD4‐1 knockdown (KD) resulted in bortezomib resistance in MM cells <italic>in vitro</italic>
and <italic>in vivo</italic>
. The overexpression (OE) of NEDD4‐1, but not an enzyme‐dead NEDD4‐1‐C867S mutant, had the opposite effect. Furthermore, the overexpression of NEDD4‐1 in NEDD4‐1 KD cells resensitized the cells to bortezomib in an add‐back rescue experiment. Mechanistically, pAkt‐Ser473 levels and Akt signaling were elevated and decreased by NEDD4‐1 KD and OE, respectively. NEDD4‐1 ubiquitinated Akt and targeted pAkt‐Ser473 for proteasomal degradation. More importantly, the NEDD4‐1 KD‐induced upregulation of Akt expression sensitized MM cells to growth inhibition after treatment with an Akt inhibitor. Collectively, our results suggest that high NEDD4‐1 levels may be a potential new therapeutic target in MM.</p>
</abstract>
<abstract abstract-type="short"><p><bold>What's new?</bold>
</p>
<p>While multiple myeloma (MM) remains an incurable disease, therapeutic advances have greatly improved its clinical management. Among the agents most effective against MM is the proteasome inhibitor bortezomib, though many patients eventually develop drug resistance. Here, decreased expression of the tumor suppressor NEDD4‐1 was found to serve a key role in modulating MM sensitivity to bortezomib. Reduced NEDD4‐1 expression was associated with increased PTEN/PI3K/Akt signaling and tumor growth. Experiments showed that NEDD4‐1 normally binds directly to Akt, enhancing its ubiquitination and thereby exerting anti‐MM effects. The data warrant further investigation of NEDD4‐1 reactivation as a novel therapeutic strategy for MM.</p>
</abstract>
<kwd-group kwd-group-type="author-generated"><kwd id="ijc32615-kwd-0001">NEDD4‐1</kwd>
<kwd id="ijc32615-kwd-0002">Akt</kwd>
<kwd id="ijc32615-kwd-0003">Bortezomib</kwd>
<kwd id="ijc32615-kwd-0004">Ubiquitination</kwd>
<kwd id="ijc32615-kwd-0005">Multiple myeloma</kwd>
</kwd-group>
<funding-group><award-group id="funding-0001"><funding-source><institution-wrap><institution> Natural Science Foundation of Zhejiang Province </institution>
<institution-id institution-id-type="open-funder-registry">10.13039/501100004731</institution-id>
</institution-wrap>
</funding-source>
<award-id>LY17H080001</award-id>
</award-group>
<award-group id="funding-0002"><funding-source>Medical and Health Science and Technology Project of Zhejiang Province</funding-source>
<award-id>2019KY380</award-id>
</award-group>
<award-group id="funding-0003"><funding-source><institution-wrap><institution>National Natural Science Foundation of China </institution>
<institution-id institution-id-type="open-funder-registry">10.13039/501100001809</institution-id>
</institution-wrap>
</funding-source>
<award-id>81770217</award-id>
<award-id>81872322</award-id>
<award-id>91742110</award-id>
</award-group>
</funding-group>
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<meta-value>1 April 2020</meta-value>
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<meta-value>Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:18.02.2020</meta-value>
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<notes><fn-group id="ijc32615-ntgp-0001"><fn id="ijc32615-note-0002"><p><bold>Author contributions:</bold>
Study and experimental design: Huang X, Cai Z. Experimental analysis and manuscript writing: Huang X, Gu H. Research and data analysis: Zhang E, Cao W, Lv N, Yan H, Chen Q. Primary sample collection: Yang L, Chen J. Supervision of the experiments: He J, Yi Q, Cai Z.</p>
</fn>
<fn id="ijc32615-note-0003"><p><bold>Conflict of interest:</bold>
None declared.</p>
</fn>
<fn id="ijc32615-note-0004"><p>[Correction added on September 16, 2019 after first online publication: figures updated.]</p>
</fn>
</fn-group>
</notes>
</front>
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