PHLPP Sensitizes Multiple Myeloma Cells to Bortezomib Through Regulating LAMP2
Identifieur interne : 000E89 ( Ncbi/Merge ); précédent : 000E88; suivant : 000E90PHLPP Sensitizes Multiple Myeloma Cells to Bortezomib Through Regulating LAMP2
Auteurs : Xiao Liu [République populaire de Chine] ; Chengyuan Li [République populaire de Chine] ; Yunfeng Fu [République populaire de Chine] ; Jing Liu [République populaire de Chine]Source :
- OncoTargets and therapy [ 1178-6930 ] ; 2020.
Abstract
Treatment of bortezomib (BTZ) improves the clinical outcomes of patients with multiple myeloma (MM). However, primary resistance and acquired resistance to BTZ frequently develop in patients with MM. PH domain leucine-rich repeat protein phosphatase (PHLPP) plays an important role in chemoresistance in a number of cancers. However, the role of PHLPP on MM remains unclear. In this study, we investigated the role of PHLPP in BTZ-resistant MM cells.
BrdU assays, immunoprecipitation, flow cytometry analyses, and immunofluorescence assays were performed.
PHLPP and lysosome-associated membrane protein 2 (LAMP2) levels were downregulated in BTZ-resistant MM cells compared with BTZ-sensitive MM cells, accompanied by inactivation of autophagy pathway evaluated by a reduction in Beclin1, Atg5 and LC3B and increase in p62. Gain- and loss-of-function experiments revealed that PHLPP partially re-sensitized MM cells to BTZ. In addition, PHLPP overexpression increased whereas PHLPP knockdown reduced LAMP2 expression, subsequently regulating the autophagy pathway in MM cells. Further findings demonstrated that LAMP2 knockdown reversed PHLPP-mediated cell apoptosis and autophagy activation in MM cells.
This study demonstrated that PHLPP is a potential strategy for overcoming BTZ resistance in patients with MM.
Url:
DOI: 10.2147/OTT.S237343
PubMed: 32021285
PubMed Central: 6969690
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<author><name sortKey="Liu, Xiao" sort="Liu, Xiao" uniqKey="Liu X" first="Xiao" last="Liu">Xiao Liu</name>
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<author><name sortKey="Li, Chengyuan" sort="Li, Chengyuan" uniqKey="Li C" first="Chengyuan" last="Li">Chengyuan Li</name>
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<author><name sortKey="Li, Chengyuan" sort="Li, Chengyuan" uniqKey="Li C" first="Chengyuan" last="Li">Chengyuan Li</name>
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,<country>People’s Republic of China</country>
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,<country>People’s Republic of China</country>
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<series><title level="j">OncoTargets and therapy</title>
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<front><div type="abstract" xml:lang="en"><sec id="S2001" sec-type="intro"><title>Introduction</title>
<p>Treatment of bortezomib (BTZ) improves the clinical outcomes of patients with multiple myeloma (MM). However, primary resistance and acquired resistance to BTZ frequently develop in patients with MM. PH domain leucine-rich repeat protein phosphatase (PHLPP) plays an important role in chemoresistance in a number of cancers. However, the role of PHLPP on MM remains unclear. In this study, we investigated the role of PHLPP in BTZ-resistant MM cells.</p>
</sec>
<sec id="S2002"><title>Methods</title>
<p>BrdU assays, immunoprecipitation, flow cytometry analyses, and immunofluorescence assays were performed.</p>
</sec>
<sec id="S2003"><title>Results</title>
<p>PHLPP and lysosome-associated membrane protein 2 (LAMP2) levels were downregulated in BTZ-resistant MM cells compared with BTZ-sensitive MM cells, accompanied by inactivation of autophagy pathway evaluated by a reduction in Beclin1, Atg5 and LC3B and increase in p62. Gain- and loss-of-function experiments revealed that PHLPP partially re-sensitized MM cells to BTZ. In addition, PHLPP overexpression increased whereas PHLPP knockdown reduced LAMP2 expression, subsequently regulating the autophagy pathway in MM cells. Further findings demonstrated that LAMP2 knockdown reversed PHLPP-mediated cell apoptosis and autophagy activation in MM cells.</p>
</sec>
<sec id="S2004"><title>Conclusion</title>
<p>This study demonstrated that PHLPP is a potential strategy for overcoming BTZ resistance in patients with MM.</p>
</sec>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Onco Targets Ther</journal-id>
<journal-id journal-id-type="iso-abbrev">Onco Targets Ther</journal-id>
<journal-id journal-id-type="publisher-id">OTT</journal-id>
<journal-id journal-id-type="pmc">ott</journal-id>
<journal-title-group><journal-title>OncoTargets and therapy</journal-title>
</journal-title-group>
<issn pub-type="epub">1178-6930</issn>
<publisher><publisher-name>Dove</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">32021285</article-id>
<article-id pub-id-type="pmc">6969690</article-id>
<article-id pub-id-type="publisher-id">237343</article-id>
<article-id pub-id-type="doi">10.2147/OTT.S237343</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject>
</subj-group>
</article-categories>
<title-group><article-title>PHLPP Sensitizes Multiple Myeloma Cells to Bortezomib Through Regulating LAMP2</article-title>
<alt-title alt-title-type="running-authors">Liu et al</alt-title>
<alt-title alt-title-type="running-title">Liu et al</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Xiao</given-names>
</name>
<xref ref-type="aff" rid="AFF0001">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Li</surname>
<given-names>Chengyuan</given-names>
</name>
<xref ref-type="aff" rid="AFF0001">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fu</surname>
<given-names>Yunfeng</given-names>
</name>
<xref ref-type="aff" rid="AFF0001">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Jing</given-names>
</name>
<xref ref-type="corresp" rid="AN0001"></xref>
<xref ref-type="aff" rid="AFF0001">1</xref>
</contrib>
<aff id="AFF0001"><label>1</label>
<institution>Department of Hematology, The Third Xiangya Hospital of Central South University</institution>
,<addr-line>Changsha</addr-line>
<addr-line>410013</addr-line>
,<country>People’s Republic of China</country>
</aff>
</contrib-group>
<author-notes><corresp id="AN0001">Correspondence: Jing Liu; Yunfeng Fu <institution>The Third Xiangya Hospital of Central South University</institution>
, <addr-line>Tongzipo Road 138</addr-line>
, <addr-line>Changsha</addr-line>
<addr-line>410013</addr-line>
, <country>People’s Republic of China</country>
<phone>Tel/Fax + 86-073188618511</phone>
Email liujing3571@163.com; fuyunfeng@csu.edu.cn</corresp>
</author-notes>
<pub-date pub-type="epub"><day>14</day>
<month>1</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="collection"><year>2020</year>
</pub-date>
<volume>13</volume>
<fpage>401</fpage>
<lpage>411</lpage>
<history><date date-type="received"><day>05</day>
<month>11</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>24</day>
<month>12</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2020 Liu et al.</copyright-statement>
<copyright-year>2020</copyright-year>
<copyright-holder>Liu et al.</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/"><license-p>This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at <ext-link ext-link-type="uri" xlink:href="https://www.dovepress.com/terms.php">https://www.dovepress.com/terms.php</ext-link>
and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link>
). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (<ext-link ext-link-type="uri" xlink:href="https://www.dovepress.com/terms.php">https://www.dovepress.com/terms.php</ext-link>
).</license-p>
</license>
</permissions>
<abstract><sec id="S2001" sec-type="intro"><title>Introduction</title>
<p>Treatment of bortezomib (BTZ) improves the clinical outcomes of patients with multiple myeloma (MM). However, primary resistance and acquired resistance to BTZ frequently develop in patients with MM. PH domain leucine-rich repeat protein phosphatase (PHLPP) plays an important role in chemoresistance in a number of cancers. However, the role of PHLPP on MM remains unclear. In this study, we investigated the role of PHLPP in BTZ-resistant MM cells.</p>
</sec>
<sec id="S2002"><title>Methods</title>
<p>BrdU assays, immunoprecipitation, flow cytometry analyses, and immunofluorescence assays were performed.</p>
</sec>
<sec id="S2003"><title>Results</title>
<p>PHLPP and lysosome-associated membrane protein 2 (LAMP2) levels were downregulated in BTZ-resistant MM cells compared with BTZ-sensitive MM cells, accompanied by inactivation of autophagy pathway evaluated by a reduction in Beclin1, Atg5 and LC3B and increase in p62. Gain- and loss-of-function experiments revealed that PHLPP partially re-sensitized MM cells to BTZ. In addition, PHLPP overexpression increased whereas PHLPP knockdown reduced LAMP2 expression, subsequently regulating the autophagy pathway in MM cells. Further findings demonstrated that LAMP2 knockdown reversed PHLPP-mediated cell apoptosis and autophagy activation in MM cells.</p>
</sec>
<sec id="S2004"><title>Conclusion</title>
<p>This study demonstrated that PHLPP is a potential strategy for overcoming BTZ resistance in patients with MM.</p>
</sec>
</abstract>
<kwd-group kwd-group-type="author"><title>Keywords</title>
<kwd>multiple myeloma</kwd>
<kwd>PHLPP</kwd>
<kwd>bortezomib</kwd>
<kwd>resistance</kwd>
<kwd>chaperone-mediated autophagy</kwd>
<kwd>LAMP2</kwd>
</kwd-group>
<funding-group><funding-statement>This work was supported by the National Natural Science Foundation of China (No. 81670203) and Natural Science Foundation of Hunan Provincial China (No. 2018JJ3776 and No. 2017JJ3463).</funding-statement>
</funding-group>
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<ref-count count="29"></ref-count>
<page-count count="11"></page-count>
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<affiliations><list><country><li>République populaire de Chine</li>
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<name sortKey="Liu, Jing" sort="Liu, Jing" uniqKey="Liu J" first="Jing" last="Liu">Jing Liu</name>
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