PHLPP Sensitizes Multiple Myeloma Cells to Bortezomib Through Regulating LAMP2
Identifieur interne : 000085 ( an2020/Analysis ); précédent : 000084; suivant : 000086PHLPP 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
Affiliations:
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PMC:6969690Le document en format XML
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University</institution>,<addr-line>Changsha</addr-line><addr-line>410013</addr-line>,<country>People’s Republic of China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Li, Chengyuan" sort="Li, Chengyuan" uniqKey="Li C" first="Chengyuan" last="Li">Chengyuan Li</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><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></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fu, Yunfeng" sort="Fu, Yunfeng" uniqKey="Fu Y" first="Yunfeng" last="Fu">Yunfeng Fu</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><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></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Jing" sort="Liu, Jing" uniqKey="Liu J" first="Jing" last="Liu">Jing Liu</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><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></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">OncoTargets and therapy</title><idno 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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><back><div1 type="bibliography"><listBibl><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><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Liu, Xiao" sort="Liu, Xiao" uniqKey="Liu X" first="Xiao" last="Liu">Xiao Liu</name></noRegion><name sortKey="Fu, Yunfeng" sort="Fu, Yunfeng" uniqKey="Fu Y" first="Yunfeng" last="Fu">Yunfeng Fu</name><name sortKey="Li, Chengyuan" sort="Li, Chengyuan" uniqKey="Li C" first="Chengyuan" last="Li">Chengyuan Li</name><name sortKey="Liu, Jing" sort="Liu, Jing" uniqKey="Liu J" first="Jing" last="Liu">Jing Liu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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