Regulatory effects of a Mnk2-eIF4E feedback loop during mTORC1 targeting of human medulloblastoma cells.
Identifieur interne : 000D91 ( Main/Corpus ); précédent : 000D90; suivant : 000D92Regulatory effects of a Mnk2-eIF4E feedback loop during mTORC1 targeting of human medulloblastoma cells.
Auteurs : Frank Eckerdt ; Elspeth Beauchamp ; Jonathan Bell ; Asneha Iqbal ; Bing Su ; Rikiro Fukunaga ; Rishi R. Lulla ; Stewart Goldman ; Leonidas C. PlataniasSource :
- Oncotarget [ 1949-2553 ] ; 2014.
English descriptors
- KwdEn :
- Antibiotics, Antineoplastic (pharmacology), Cell Line, Tumor (MeSH), Cell Proliferation (drug effects), Cell Survival (drug effects), Cerebellar Neoplasms (enzymology), Cerebellar Neoplasms (genetics), Cerebellar Neoplasms (pathology), Dose-Response Relationship, Drug (MeSH), Drug Resistance, Neoplasm (MeSH), Eukaryotic Initiation Factor-4E (genetics), Eukaryotic Initiation Factor-4E (metabolism), Feedback, Physiological (MeSH), Humans (MeSH), Intracellular Signaling Peptides and Proteins (genetics), Intracellular Signaling Peptides and Proteins (metabolism), Mechanistic Target of Rapamycin Complex 1 (MeSH), Medulloblastoma (enzymology), Medulloblastoma (genetics), Medulloblastoma (pathology), Multiprotein Complexes (antagonists & inhibitors), Multiprotein Complexes (metabolism), Phosphorylation (MeSH), Protein Kinase Inhibitors (pharmacology), Protein-Serine-Threonine Kinases (genetics), Protein-Serine-Threonine Kinases (metabolism), RNA Interference (MeSH), Signal Transduction (drug effects), Sirolimus (pharmacology), TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (metabolism), Transfection (MeSH).
- MESH :
- chemical , antagonists & inhibitors : Multiprotein Complexes, TOR Serine-Threonine Kinases.
- chemical , genetics : Eukaryotic Initiation Factor-4E, Intracellular Signaling Peptides and Proteins, Protein-Serine-Threonine Kinases.
- chemical , metabolism : Eukaryotic Initiation Factor-4E, Intracellular Signaling Peptides and Proteins, Multiprotein Complexes, Protein-Serine-Threonine Kinases, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Antibiotics, Antineoplastic, Protein Kinase Inhibitors, Sirolimus.
- drug effects : Cell Proliferation, Cell Survival, Signal Transduction.
- enzymology : Cerebellar Neoplasms, Medulloblastoma.
- genetics : Cerebellar Neoplasms, Medulloblastoma.
- pathology : Cerebellar Neoplasms, Medulloblastoma.
- Cell Line, Tumor, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Feedback, Physiological, Humans, Mechanistic Target of Rapamycin Complex 1, Phosphorylation, RNA Interference, Transfection.
Abstract
The mTOR pathway controls mRNA translation of mitogenic proteins and is a central regulator of metabolism in malignant cells. Development of malignant cell resistance is a limiting factor to the effects of mTOR inhibitors, but the mechanisms accounting for such resistance are not well understood. We provide evidence that mTORC1 inhibition by rapamycin results in engagement of a negative feedback regulatory loop in malignant medulloblastoma cells, involving phosphorylation of the eukaryotic translation-initiation factor eIF4E. This eIF4E phosphorylation is Mnk2- mediated, but Mnk1-independent, and acts as a survival mechanism for medulloblastoma cells. Pharmacological targeting of Mnk1/2 or siRNA-mediated knockdown of Mnk2 sensitizes medulloblastoma cells to mTOR inhibition and promotes suppression of malignant cell proliferation and anchorage-independent growth. Altogether, these findings provide evidence for the existence of a Mnk2-controlled feedback loop in medulloblastoma cells that accounts for resistance to mTOR inhibitors, and raise the potential for combination treatments of mTOR and Mnk inhibitors for the treatment of medulloblastoma.
DOI: 10.18632/oncotarget.2319
PubMed: 25193863
PubMed Central: PMC4226695
Links to Exploration step
pubmed:25193863Le document en format XML
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Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA.</nlm:affiliation></affiliation></author><author><name sortKey="Beauchamp, Elspeth" sort="Beauchamp, Elspeth" uniqKey="Beauchamp E" first="Elspeth" last="Beauchamp">Elspeth Beauchamp</name><affiliation><nlm:affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Bell, Jonathan" sort="Bell, Jonathan" uniqKey="Bell J" first="Jonathan" last="Bell">Jonathan Bell</name><affiliation><nlm:affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA.</nlm:affiliation></affiliation></author><author><name sortKey="Iqbal, Asneha" sort="Iqbal, Asneha" uniqKey="Iqbal A" first="Asneha" last="Iqbal">Asneha Iqbal</name><affiliation><nlm:affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Division of Hematology and Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Su, Bing" sort="Su, Bing" uniqKey="Su B" first="Bing" last="Su">Bing Su</name><affiliation><nlm:affiliation>Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA; Shanghai Institute of Immunology Department of Microbiology and Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China.</nlm:affiliation></affiliation></author><author><name sortKey="Fukunaga, Rikiro" sort="Fukunaga, Rikiro" uniqKey="Fukunaga R" first="Rikiro" last="Fukunaga">Rikiro Fukunaga</name><affiliation><nlm:affiliation>Laboratory of Biochemistry, Osaka University of Pharmaceutical Sciences, Osaka, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Lulla, Rishi R" sort="Lulla, Rishi R" uniqKey="Lulla R" first="Rishi R" last="Lulla">Rishi R. Lulla</name><affiliation><nlm:affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Division of Hematology and Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Goldman, Stewart" sort="Goldman, Stewart" uniqKey="Goldman S" first="Stewart" last="Goldman">Stewart Goldman</name><affiliation><nlm:affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Division of Hematology and Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Platanias, Leonidas C" sort="Platanias, Leonidas C" uniqKey="Platanias L" first="Leonidas C" last="Platanias">Leonidas C. Platanias</name><affiliation><nlm:affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antibiotics, Antineoplastic (pharmacology)</term><term>Cell Line, Tumor (MeSH)</term><term>Cell Proliferation (drug effects)</term><term>Cell Survival (drug effects)</term><term>Cerebellar Neoplasms (enzymology)</term><term>Cerebellar Neoplasms (genetics)</term><term>Cerebellar Neoplasms (pathology)</term><term>Dose-Response Relationship, Drug (MeSH)</term><term>Drug Resistance, Neoplasm (MeSH)</term><term>Eukaryotic Initiation Factor-4E (genetics)</term><term>Eukaryotic Initiation Factor-4E (metabolism)</term><term>Feedback, Physiological (MeSH)</term><term>Humans (MeSH)</term><term>Intracellular Signaling Peptides and Proteins (genetics)</term><term>Intracellular Signaling Peptides and Proteins (metabolism)</term><term>Mechanistic Target of Rapamycin Complex 1 (MeSH)</term><term>Medulloblastoma (enzymology)</term><term>Medulloblastoma (genetics)</term><term>Medulloblastoma (pathology)</term><term>Multiprotein Complexes (antagonists & inhibitors)</term><term>Multiprotein Complexes (metabolism)</term><term>Phosphorylation (MeSH)</term><term>Protein Kinase Inhibitors (pharmacology)</term><term>Protein-Serine-Threonine Kinases (genetics)</term><term>Protein-Serine-Threonine Kinases (metabolism)</term><term>RNA Interference (MeSH)</term><term>Signal Transduction (drug effects)</term><term>Sirolimus (pharmacology)</term><term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term><term>TOR Serine-Threonine Kinases (metabolism)</term><term>Transfection (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Multiprotein Complexes</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Eukaryotic Initiation Factor-4E</term><term>Intracellular Signaling Peptides and Proteins</term><term>Protein-Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Eukaryotic Initiation Factor-4E</term><term>Intracellular Signaling Peptides and Proteins</term><term>Multiprotein Complexes</term><term>Protein-Serine-Threonine Kinases</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antibiotics, Antineoplastic</term><term>Protein Kinase Inhibitors</term><term>Sirolimus</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Proliferation</term><term>Cell Survival</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Cerebellar Neoplasms</term><term>Medulloblastoma</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Cerebellar Neoplasms</term><term>Medulloblastoma</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Cerebellar Neoplasms</term><term>Medulloblastoma</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Dose-Response Relationship, Drug</term><term>Drug Resistance, Neoplasm</term><term>Feedback, Physiological</term><term>Humans</term><term>Mechanistic Target of Rapamycin Complex 1</term><term>Phosphorylation</term><term>RNA Interference</term><term>Transfection</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The mTOR pathway controls mRNA translation of mitogenic proteins and is a central regulator of metabolism in malignant cells. Development of malignant cell resistance is a limiting factor to the effects of mTOR inhibitors, but the mechanisms accounting for such resistance are not well understood. We provide evidence that mTORC1 inhibition by rapamycin results in engagement of a negative feedback regulatory loop in malignant medulloblastoma cells, involving phosphorylation of the eukaryotic translation-initiation factor eIF4E. This eIF4E phosphorylation is Mnk2- mediated, but Mnk1-independent, and acts as a survival mechanism for medulloblastoma cells. Pharmacological targeting of Mnk1/2 or siRNA-mediated knockdown of Mnk2 sensitizes medulloblastoma cells to mTOR inhibition and promotes suppression of malignant cell proliferation and anchorage-independent growth. Altogether, these findings provide evidence for the existence of a Mnk2-controlled feedback loop in medulloblastoma cells that accounts for resistance to mTOR inhibitors, and raise the potential for combination treatments of mTOR and Mnk inhibitors for the treatment of medulloblastoma. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25193863</PMID><DateCompleted><Year>2015</Year><Month>06</Month><Day>25</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1949-2553</ISSN><JournalIssue CitedMedium="Internet"><Volume>5</Volume><Issue>18</Issue><PubDate><Year>2014</Year><Month>Sep</Month><Day>30</Day></PubDate></JournalIssue><Title>Oncotarget</Title><ISOAbbreviation>Oncotarget</ISOAbbreviation></Journal><ArticleTitle>Regulatory effects of a Mnk2-eIF4E feedback loop during mTORC1 targeting of human medulloblastoma cells.</ArticleTitle><Pagination><MedlinePgn>8442-51</MedlinePgn></Pagination><Abstract><AbstractText>The mTOR pathway controls mRNA translation of mitogenic proteins and is a central regulator of metabolism in malignant cells. Development of malignant cell resistance is a limiting factor to the effects of mTOR inhibitors, but the mechanisms accounting for such resistance are not well understood. We provide evidence that mTORC1 inhibition by rapamycin results in engagement of a negative feedback regulatory loop in malignant medulloblastoma cells, involving phosphorylation of the eukaryotic translation-initiation factor eIF4E. This eIF4E phosphorylation is Mnk2- mediated, but Mnk1-independent, and acts as a survival mechanism for medulloblastoma cells. Pharmacological targeting of Mnk1/2 or siRNA-mediated knockdown of Mnk2 sensitizes medulloblastoma cells to mTOR inhibition and promotes suppression of malignant cell proliferation and anchorage-independent growth. Altogether, these findings provide evidence for the existence of a Mnk2-controlled feedback loop in medulloblastoma cells that accounts for resistance to mTOR inhibitors, and raise the potential for combination treatments of mTOR and Mnk inhibitors for the treatment of medulloblastoma. </AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Eckerdt</LastName><ForeName>Frank</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Beauchamp</LastName><ForeName>Elspeth</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bell</LastName><ForeName>Jonathan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Iqbal</LastName><ForeName>Asneha</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Division of Hematology and Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Su</LastName><ForeName>Bing</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA; Shanghai Institute of Immunology Department of Microbiology and Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fukunaga</LastName><ForeName>Rikiro</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Laboratory of Biochemistry, Osaka University of Pharmaceutical Sciences, Osaka, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lulla</LastName><ForeName>Rishi R</ForeName><Initials>RR</Initials><AffiliationInfo><Affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Division of Hematology and Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Goldman</LastName><ForeName>Stewart</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Division of Hematology and Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Platanias</LastName><ForeName>Leonidas C</ForeName><Initials>LC</Initials><AffiliationInfo><Affiliation>Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 CA121192</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 CA077816</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>I01 CX000916</GrantID><Acronym>CX</Acronym><Agency>CSRD VA</Agency><Country>United States</Country></Grant><Grant><GrantID>T32 CA009560</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 CA155566</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>CA77816</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 CA060553</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>T32CA070085</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>T32 CA070085</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>CA155566</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>CA121192</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013486">Research Support, U.S. Gov't, Non-P.H.S.</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Oncotarget</MedlineTA><NlmUniqueID>101532965</NlmUniqueID><ISSNLinking>1949-2553</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000903">Antibiotics, Antineoplastic</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D039561">Eukaryotic Initiation Factor-4E</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D047908">Intracellular Signaling Peptides and Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D046912">Multiprotein Complexes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D047428">Protein Kinase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance 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