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dc.contributor.authorKomatsu, Naokija
dc.contributor.authorFujita, Yoshihisaja
dc.contributor.authorMatsuda, Michiyukija
dc.contributor.authorAoki, Kazuhiroja
dc.contributor.alternative青木, 一洋ja
dc.date.accessioned2016-03-02T05:22:26Z-
dc.date.available2016-03-02T05:22:26Z-
dc.date.issued2015-11-05ja
dc.identifier.issn1476-5594ja
dc.identifier.urihttp://hdl.handle.net/2433/207613-
dc.description.abstractCancer cells harboring oncogenic BRaf mutants, but not oncogenic KRas mutants, are sensitive to MEK inhibitors (MEKi). The mechanism underlying the intrinsic resistance to MEKi in KRas-mutant cells is under intensive investigation. Here, we pursued this mechanism by live imaging of extracellular signal-regulated kinases (ERK) and mammalian target of rapamycin complex 1 (mTORC1) activities in oncogenic KRas or BRaf-mutant cancer cells. We established eight cancer cell lines expressing Förster resonance energy transfer (FRET) biosensors for ERK activity and S6K activity, which was used as a surrogate marker for mTORC1 activity. Under increasing concentrations of MEKi, ERK activity correlated linearly with the cell growth rate in BRaf-mutant cancer cells, but not KRas-mutant cancer cells. The administration of PI3K inhibitors resulted in a linear correlation between ERK activity and cell growth rate in KRas-mutant cancer cells. Intriguingly, mTORC1 activity was correlated linearly with the cell growth rate in both BRaf-mutant cancer cells and KRas-mutant cancer cells. These observations suggested that mTORC1 activity had a pivotal role in cell growth and that the mTORC1 activity was maintained primarily by the ERK pathway in BRaf-mutant cancer cells and by both the ERK and PI3K pathways in KRas-mutant cancer cells. FRET imaging revealed that MEKi inhibited mTORC1 activity with slow kinetics, implying transcriptional control of mTORC1 activity by ERK. In agreement with this observation, MEKi induced the expression of negative regulators of mTORC1, including TSC1, TSC2 and Deptor, which occurred more significantly in BRaf-mutant cells than in KRas-mutant cells. These findings suggested that the suppression of mTORC1 activity and induction of negative regulators of mTORC1 in cancer cells treated for at least 1 day could be used as surrogate markers for the MEKi sensitivity of cancer cells.ja
dc.format.mimetypeapplication/pdfja
dc.language.isoengja
dc.publisherNature Publishing Groupja
dc.rightsThis is the accepted manuscrip of the article is available at http://dx.doi.org/10.1038/onc.2015.16.ja
dc.rightsThe full-text file will be made open to the public on 5 May 2016 in accordance with publisher's 'Terms and Conditions for Self-Archiving'.ja
dc.rightsこの論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。This is not the published version. Please cite only the published version.ja
dc.subject.meshCell Line, Tumorja
dc.subject.meshExtracellular Signal-Regulated MAP Kinases/antagonists & inhibitorsja
dc.subject.meshExtracellular Signal-Regulated MAP Kinases/geneticsja
dc.subject.meshExtracellular Signal-Regulated MAP Kinases/metabolismja
dc.subject.meshGene Expression Regulation, Neoplastic/drug effectsja
dc.subject.meshHumansja
dc.subject.meshIntracellular Signaling Peptides and Proteins/geneticsja
dc.subject.meshIntracellular Signaling Peptides and Proteins/metabolismja
dc.subject.meshMAP Kinase Signaling System/drug effectsja
dc.subject.meshMAP Kinase Signaling System/geneticsja
dc.subject.meshMultiprotein Complexes/biosynthesisja
dc.subject.meshMultiprotein Complexes/geneticsja
dc.subject.meshMutationja
dc.subject.meshNeoplasms/drug therapyja
dc.subject.meshNeoplasms/geneticsja
dc.subject.meshNeoplasms/metabolismja
dc.subject.meshPhosphatidylinositol 3-Kinases/geneticsja
dc.subject.meshPhosphatidylinositol 3-Kinases/metabolismja
dc.subject.meshProtein Kinase Inhibitors/pharmacologyja
dc.subject.meshProto-Oncogene Proteins/geneticsja
dc.subject.meshProto-Oncogene Proteins/metabolismja
dc.subject.meshProto-Oncogene Proteins B-raf/geneticsja
dc.subject.meshProto-Oncogene Proteins B-raf/metabolismja
dc.subject.meshTOR Serine-Threonine Kinases/biosynthesisja
dc.subject.meshTOR Serine-Threonine Kinases/geneticsja
dc.subject.meshTelomerase/geneticsja
dc.subject.meshTelomerase/metabolismja
dc.subject.meshTumor Suppressor Proteins/geneticsja
dc.subject.meshTumor Suppressor Proteins/metabolismja
dc.subject.meshUp-Regulation/drug effectsja
dc.subject.meshras Proteins/geneticsja
dc.subject.meshras Proteins/metabolismja
dc.titlemTORC1 upregulation via ERK-dependent gene expression change confers intrinsic resistance to MEK inhibitors in oncogenic KRas-mutant cancer cells.ja
dc.type.niitypeJournal Articleja
dc.identifier.ncidAA10687380ja
dc.identifier.jtitleOncogeneja
dc.identifier.volume34ja
dc.identifier.issue45ja
dc.identifier.spage5607ja
dc.identifier.epage5616ja
dc.relation.doi10.1038/onc.2015.16ja
dc.textversionauthorja
dc.startdate.bitstreamsavailable2016-05-05ja
dc.identifier.pmid25703330ja
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