The NEDD4‐1 E3 ubiquitin ligase: A potential molecular target for bortezomib sensitivity in multiple myeloma
Identifieur interne : 000361 ( Main/Exploration ); précédent : 000360; suivant : 000362The 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
Affiliations:
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sort="Cao, Wen" uniqKey="Cao W" first="Wen" last="Cao">Wen Cao</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Yan, Haimeng" sort="Yan, Haimeng" uniqKey="Yan H" first="Haimeng" last="Yan">Haimeng Yan</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Chen, Jing" sort="Chen, Jing" uniqKey="Chen J" first="Jing" last="Chen">Jing Chen</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Yang, Li" sort="Yang, Li" uniqKey="Yang L" first="Li" last="Yang">Li Yang</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Lv, Ning" sort="Lv, Ning" uniqKey="Lv N" first="Ning" last="Lv">Ning Lv</name><affiliation><nlm:aff id="ijc32615-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="He, Jingsong" sort="He, Jingsong" uniqKey="He J" first="Jingsong" last="He">Jingsong 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id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Gu, Huiyao" sort="Gu, Huiyao" uniqKey="Gu H" first="Huiyao" last="Gu">Huiyao Gu</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Enfan" sort="Zhang, Enfan" uniqKey="Zhang E" first="Enfan" last="Zhang">Enfan Zhang</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Chen, Qingxiao" sort="Chen, Qingxiao" uniqKey="Chen Q" first="Qingxiao" last="Chen">Qingxiao Chen</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Cao, Wen" sort="Cao, Wen" uniqKey="Cao W" first="Wen" last="Cao">Wen Cao</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Yan, Haimeng" sort="Yan, Haimeng" uniqKey="Yan H" first="Haimeng" last="Yan">Haimeng Yan</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Chen, Jing" sort="Chen, Jing" uniqKey="Chen J" first="Jing" last="Chen">Jing Chen</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Yang, Li" sort="Yang, Li" uniqKey="Yang L" first="Li" last="Yang">Li Yang</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Lv, Ning" sort="Lv, Ning" uniqKey="Lv N" first="Ning" last="Lv">Ning Lv</name><affiliation><nlm:aff id="ijc32615-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="He, Jingsong" sort="He, Jingsong" uniqKey="He J" first="Jingsong" last="He">Jingsong He</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Yi, Qing" sort="Yi, Qing" uniqKey="Yi Q" first="Qing" last="Yi">Qing Yi</name><affiliation><nlm:aff id="ijc32615-aff-0003"></nlm:aff></affiliation></author><author><name sortKey="Cai, Zhen" sort="Cai, Zhen" uniqKey="Cai Z" first="Zhen" last="Cai">Zhen Cai</name><affiliation><nlm:aff id="ijc32615-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc32615-aff-0004"></nlm:aff></affiliation></author></analytic><series><title level="j">International Journal of Cancer</title><idno type="ISSN">0020-7136</idno><idno type="eISSN">1097-0215</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>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></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Noone, Am" uniqKey="Noone A">AM Noone</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><affiliations><list></list><tree><noCountry><name sortKey="Cai, Zhen" sort="Cai, Zhen" uniqKey="Cai Z" first="Zhen" last="Cai">Zhen Cai</name><name sortKey="Cao, Wen" sort="Cao, Wen" uniqKey="Cao W" first="Wen" last="Cao">Wen Cao</name><name sortKey="Chen, Jing" sort="Chen, Jing" uniqKey="Chen J" first="Jing" last="Chen">Jing Chen</name><name sortKey="Chen, Qingxiao" sort="Chen, Qingxiao" uniqKey="Chen Q" first="Qingxiao" last="Chen">Qingxiao Chen</name><name sortKey="Gu, Huiyao" sort="Gu, Huiyao" uniqKey="Gu H" first="Huiyao" last="Gu">Huiyao Gu</name><name sortKey="He, Jingsong" sort="He, Jingsong" uniqKey="He J" first="Jingsong" last="He">Jingsong He</name><name sortKey="Huang, Xi" sort="Huang, Xi" uniqKey="Huang X" first="Xi" last="Huang">Xi Huang</name><name sortKey="Lv, Ning" sort="Lv, Ning" uniqKey="Lv N" first="Ning" last="Lv">Ning Lv</name><name sortKey="Yan, Haimeng" sort="Yan, Haimeng" uniqKey="Yan H" first="Haimeng" last="Yan">Haimeng Yan</name><name sortKey="Yang, Li" sort="Yang, Li" uniqKey="Yang L" first="Li" last="Yang">Li Yang</name><name sortKey="Yi, Qing" sort="Yi, Qing" uniqKey="Yi Q" first="Qing" last="Yi">Qing Yi</name><name sortKey="Zhang, Enfan" sort="Zhang, Enfan" uniqKey="Zhang E" first="Enfan" last="Zhang">Enfan Zhang</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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