RapamycinFungusV1, Main, Exploration, bibRecord, 000B22

Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells.

Identifieur interne : 000B22 ( Main/Exploration ); précédent : 000B21; suivant : 000B23

Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells.

Auteurs : Yijiang Shi [États-Unis] ; Tracy R. Daniels-Wells [États-Unis] ; Patrick Frost [États-Unis] ; Jihye Lee [États-Unis] ; Richard S. Finn [États-Unis] ; Carolyne Bardeleben [États-Unis] ; Manuel L. Penichet [États-Unis] ; Michael E. Jung [États-Unis] ; Joseph Gera [États-Unis] ; Alan Lichtenstein [États-Unis]

Source :

Cancer research [ 1538-7445 ] ; 2016.

RBID : pubmed:27530328

Descripteurs français

English descriptors

KwdEn :
- Animals (MeSH), Carcinoma, Hepatocellular (drug therapy), Carcinoma, Hepatocellular (pathology), Cell Line, Tumor (MeSH), Cyclin-Dependent Kinase Inhibitor p21 (physiology), Humans (MeSH), Intracellular Signaling Peptides and Proteins (antagonists & inhibitors), Liver Neoplasms (drug therapy), Liver Neoplasms (pathology), Mechanistic Target of Rapamycin Complex 1 (MeSH), Mice (MeSH), Multiple Myeloma (drug therapy), Multiple Myeloma (pathology), Multiprotein Complexes (physiology), Proto-Oncogene Proteins c-bcl-2 (physiology), TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (physiology).
MESH :
- chemical , antagonists & inhibitors : Intracellular Signaling Peptides and Proteins, TOR Serine-Threonine Kinases.
- chemical , physiology : Cyclin-Dependent Kinase Inhibitor p21, Multiprotein Complexes, Proto-Oncogene Proteins c-bcl-2, TOR Serine-Threonine Kinases.
- drug therapy : Carcinoma, Hepatocellular, Liver Neoplasms, Multiple Myeloma.
- pathology : Carcinoma, Hepatocellular, Liver Neoplasms, Multiple Myeloma.
- Animals, Cell Line, Tumor, Humans, Mechanistic Target of Rapamycin Complex 1, Mice.

Abstract

DEPTOR is a 48 kDa protein that binds to mTOR and inhibits this kinase in TORC1 and TORC2 complexes. Overexpression of DEPTOR specifically occurs in a model of multiple myeloma. Its silencing in multiple myeloma cells is sufficient to induce cytotoxicity, suggesting that DEPTOR is a potential therapeutic target. mTORC1 paralysis protects multiple myeloma cells against DEPTOR silencing, implicating mTORC1 in the critical role of DEPTOR in multiple myeloma cell viability. Building on this foundation, we interrogated a small-molecule library for compounds that prevent DEPTOR binding to mTOR in a yeast-two-hybrid assay. One compound was identified that also prevented DEPTOR-mTOR binding in human myeloma cells, with subsequent activation of mTORC1 and mTORC2. In a surface plasmon resonance (SPR) assay, the compound bound to recombinant DEPTOR but not to mTOR. The drug also prevented binding of recombinant DEPTOR to mTOR in the SPR assay. Remarkably, although activating TORC1 and TORC2, the compound induced apoptosis and cell-cycle arrest in multiple myeloma cell lines and prevented outgrowth of human multiple myeloma cells in immunodeficient mice. In vitro cytotoxicity against multiple myeloma cell lines was directly correlated with DEPTOR protein expression and was mediated, in part, by the activation of TORC1 and induction of p21 expression. Additional cytotoxicity was seen against primary multiple myeloma cells, whereas normal hematopoietic colony formation was unaffected. These results further support DEPTOR as a viable therapeutic target in multiple myeloma and suggest an effective strategy of preventing binding of DEPTOR to mTOR. Cancer Res; 76(19); 5822-31. ©2016 AACR.

DOI: 10.1158/0008-5472.CAN-16-1019
PubMed: 27530328
PubMed Central: PMC5100807

Affiliations:

Links toward previous steps (curation, corpus...)

to stream Main, to step Corpus: 000992
to stream Main, to step Curation: 000992

Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term>
<term>Carcinoma, Hepatocellular (drug therapy)</term>
<term>Carcinoma, Hepatocellular (pathology)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Cyclin-Dependent Kinase Inhibitor p21 (physiology)</term>
<term>Humans (MeSH)</term>
<term>Intracellular Signaling Peptides and Proteins (antagonists & inhibitors)</term>
<term>Liver Neoplasms (drug therapy)</term>
<term>Liver Neoplasms (pathology)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (MeSH)</term>
<term>Mice (MeSH)</term>
<term>Multiple Myeloma (drug therapy)</term>
<term>Multiple Myeloma (pathology)</term>
<term>Multiprotein Complexes (physiology)</term>
<term>Proto-Oncogene Proteins c-bcl-2 (physiology)</term>
<term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term>
<term>TOR Serine-Threonine Kinases (physiology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term>
<term>Carcinome hépatocellulaire (anatomopathologie)</term>
<term>Carcinome hépatocellulaire (traitement médicamenteux)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (MeSH)</term>
<term>Complexes multiprotéiques (physiologie)</term>
<term>Humains (MeSH)</term>
<term>Inhibiteur p21 de kinase cycline-dépendante (physiologie)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Myélome multiple (anatomopathologie)</term>
<term>Myélome multiple (traitement médicamenteux)</term>
<term>Protéines et peptides de signalisation intracellulaire (antagonistes et inhibiteurs)</term>
<term>Protéines proto-oncogènes c-bcl-2 (physiologie)</term>
<term>Souris (MeSH)</term>
<term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term>
<term>Sérine-thréonine kinases TOR (physiologie)</term>
<term>Tumeurs du foie (anatomopathologie)</term>
<term>Tumeurs du foie (traitement médicamenteux)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Intracellular Signaling Peptides and Proteins</term>
<term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Cyclin-Dependent Kinase Inhibitor p21</term>
<term>Multiprotein Complexes</term>
<term>Proto-Oncogene Proteins c-bcl-2</term>
<term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Carcinome hépatocellulaire</term>
<term>Myélome multiple</term>
<term>Tumeurs du foie</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines et peptides de signalisation intracellulaire</term>
<term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Carcinoma, Hepatocellular</term>
<term>Liver Neoplasms</term>
<term>Multiple Myeloma</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Carcinoma, Hepatocellular</term>
<term>Liver Neoplasms</term>
<term>Multiple Myeloma</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Complexes multiprotéiques</term>
<term>Inhibiteur p21 de kinase cycline-dépendante</term>
<term>Protéines proto-oncogènes c-bcl-2</term>
<term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Carcinome hépatocellulaire</term>
<term>Myélome multiple</term>
<term>Tumeurs du foie</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line, Tumor</term>
<term>Humans</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Mice</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Souris</term>
</keywords>
</textClass>
</profileDesc>
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<front><div type="abstract" xml:lang="en">DEPTOR is a 48 kDa protein that binds to mTOR and inhibits this kinase in TORC1 and TORC2 complexes. Overexpression of DEPTOR specifically occurs in a model of multiple myeloma. Its silencing in multiple myeloma cells is sufficient to induce cytotoxicity, suggesting that DEPTOR is a potential therapeutic target. mTORC1 paralysis protects multiple myeloma cells against DEPTOR silencing, implicating mTORC1 in the critical role of DEPTOR in multiple myeloma cell viability. Building on this foundation, we interrogated a small-molecule library for compounds that prevent DEPTOR binding to mTOR in a yeast-two-hybrid assay. One compound was identified that also prevented DEPTOR-mTOR binding in human myeloma cells, with subsequent activation of mTORC1 and mTORC2. In a surface plasmon resonance (SPR) assay, the compound bound to recombinant DEPTOR but not to mTOR. The drug also prevented binding of recombinant DEPTOR to mTOR in the SPR assay. Remarkably, although activating TORC1 and TORC2, the compound induced apoptosis and cell-cycle arrest in multiple myeloma cell lines and prevented outgrowth of human multiple myeloma cells in immunodeficient mice. In vitro cytotoxicity against multiple myeloma cell lines was directly correlated with DEPTOR protein expression and was mediated, in part, by the activation of TORC1 and induction of p21 expression. Additional cytotoxicity was seen against primary multiple myeloma cells, whereas normal hematopoietic colony formation was unaffected. These results further support DEPTOR as a viable therapeutic target in multiple myeloma and suggest an effective strategy of preventing binding of DEPTOR to mTOR. Cancer Res; 76(19); 5822-31. ©2016 AACR.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27530328</PMID>
<DateCompleted><Year>2017</Year>
<Month>08</Month>
<Day>04</Day>
</DateCompleted>
<DateRevised><Year>2018</Year>
<Month>11</Month>
<Day>13</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1538-7445</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>76</Volume>
<Issue>19</Issue>
<PubDate><Year>2016</Year>
<Month>10</Month>
<Day>01</Day>
</PubDate>
</JournalIssue>
<Title>Cancer research</Title>
<ISOAbbreviation>Cancer Res</ISOAbbreviation>
</Journal>
<ArticleTitle>Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells.</ArticleTitle>
<Pagination><MedlinePgn>5822-5831</MedlinePgn>
</Pagination>
<Abstract><AbstractText>DEPTOR is a 48 kDa protein that binds to mTOR and inhibits this kinase in TORC1 and TORC2 complexes. Overexpression of DEPTOR specifically occurs in a model of multiple myeloma. Its silencing in multiple myeloma cells is sufficient to induce cytotoxicity, suggesting that DEPTOR is a potential therapeutic target. mTORC1 paralysis protects multiple myeloma cells against DEPTOR silencing, implicating mTORC1 in the critical role of DEPTOR in multiple myeloma cell viability. Building on this foundation, we interrogated a small-molecule library for compounds that prevent DEPTOR binding to mTOR in a yeast-two-hybrid assay. One compound was identified that also prevented DEPTOR-mTOR binding in human myeloma cells, with subsequent activation of mTORC1 and mTORC2. In a surface plasmon resonance (SPR) assay, the compound bound to recombinant DEPTOR but not to mTOR. The drug also prevented binding of recombinant DEPTOR to mTOR in the SPR assay. Remarkably, although activating TORC1 and TORC2, the compound induced apoptosis and cell-cycle arrest in multiple myeloma cell lines and prevented outgrowth of human multiple myeloma cells in immunodeficient mice. In vitro cytotoxicity against multiple myeloma cell lines was directly correlated with DEPTOR protein expression and was mediated, in part, by the activation of TORC1 and induction of p21 expression. Additional cytotoxicity was seen against primary multiple myeloma cells, whereas normal hematopoietic colony formation was unaffected. These results further support DEPTOR as a viable therapeutic target in multiple myeloma and suggest an effective strategy of preventing binding of DEPTOR to mTOR. Cancer Res; 76(19); 5822-31. ©2016 AACR.</AbstractText>
<CopyrightInformation>©2016 American Association for Cancer Research.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Shi</LastName>
<ForeName>Yijiang</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Department of Hematology-Oncology, University of California at Los Angeles, Los Angeles, California.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Daniels-Wells</LastName>
<ForeName>Tracy R</ForeName>
<Initials>TR</Initials>
<AffiliationInfo><Affiliation>Department of Surgery, University of California at Los Angeles, Los Angeles, California.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Frost</LastName>
<ForeName>Patrick</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Department of Hematology-Oncology, University of California at Los Angeles, Los Angeles, California.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lee</LastName>
<ForeName>Jihye</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Finn</LastName>
<ForeName>Richard S</ForeName>
<Initials>RS</Initials>
<AffiliationInfo><Affiliation>Department of Hematology-Oncology, University of California at Los Angeles, Los Angeles, California.</Affiliation>
</AffiliationInfo>
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	Serveur d'exploration sur la rapamycine et les champignons
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Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells.

Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells.

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