Mostrar el registro sencillo del ítem
dc.contributor.author | Pudelko, Linda | |
dc.contributor.author | Rouhi, Pegah | |
dc.contributor.author | Sanjiv, Kumar | |
dc.contributor.author | Gad, Helge | |
dc.contributor.author | Kalderén, Christina | |
dc.contributor.author | Höglund, Andreas | |
dc.contributor.author | Squatrito, Massimo | |
dc.contributor.author | Schuhmacher, Alberto J | |
dc.contributor.author | Edwards, Steven | |
dc.contributor.author | Hägerstrand, Daniel | |
dc.contributor.author | Berglund, Ulrika Warpman | |
dc.contributor.author | Helleday, Thomas | |
dc.contributor.author | Bräutigam, Lars | |
dc.date.accessioned | 2019-03-20T13:21:33Z | |
dc.date.available | 2019-03-20T13:21:33Z | |
dc.date.issued | 2017-10-17 | |
dc.identifier.citation | Oncotarget. 2017;8(49):84671-84684. | es_ES |
dc.identifier.issn | 1949-2553 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/7360 | |
dc.description.abstract | Glioblastoma multiforme (GBM) is an aggressive form of brain cancer with poor prognosis. Cancer cells are characterized by a specific redox environment that adjusts metabolism to its specific needs and allows the tumor to grow and metastasize. As a consequence, cancer cells and especially GBM cells suffer from elevated oxidative pressure which requires antioxidant-defense and other sanitation enzymes to be upregulated. MTH1, which degrades oxidized nucleotides, is one of these defense enzymes and represents a promising cancer target. We found MTH1 expression levels elevated and correlated with GBM aggressiveness and discovered that siRNA knock-down or inhibition of MTH1 with small molecules efficiently reduced viability of patient-derived GBM cultures. The effect of MTH1 loss on GBM viability was likely mediated through incorporation of oxidized nucleotides and subsequent DNA damage. We revealed that MTH1 inhibition targets GBM independent of aggressiveness as well as potently kills putative GBM stem cells in vitro. We used an orthotopic zebrafish model to confirm our results in vivo and light-sheet microscopy to follow the effect of MTH1 inhibition in GBM in real time. In conclusion, MTH1 represents a promising target for GBM therapy and MTH1 inhibitors may also be effective in patients that suffer from recurring disease. | es_ES |
dc.description.sponsorship | We thank the staff of the zebrafish core facility for their excellent service, K.Edfelt and C.Sjögren for administrative help, S.Eriksson and F.Pineiro for lab support, and J.Carreras-Puigvert for help with the cell profiler software. We acknowledge M.Scobie, K.Vallin, T.Koolmeister, M.Henriksson, O.Wallner and S.Jacques for synthesis of MTH1 inhibitors and M.Guo and M.Nister for providing the GBM cultures (all Karolinska Institutet). | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Impact Journals | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject | DNA damage | es_ES |
dc.subject | MTH1 | es_ES |
dc.subject | Nudt1 | es_ES |
dc.subject | Cancer stem cells | es_ES |
dc.subject | Glioblastoma multiforme | es_ES |
dc.subject.mesh | DNA Damage | es_ES |
dc.subject.mesh | Nudt1 | es_ES |
dc.subject.mesh | glioblastoma multiforme | es_ES |
dc.subject.mesh | MTH1 | es_ES |
dc.subject.mesh | cancer stem cells | es_ES |
dc.title | Glioblastoma and glioblastoma stem cells are dependent on functional MTH1 | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 29156675 | es_ES |
dc.format.volume | 8 | es_ES |
dc.format.number | 49 | es_ES |
dc.format.page | 84671-84684 | es_ES |
dc.identifier.doi | 10.18632/oncotarget.19404 | es_ES |
dc.contributor.funder | Fundación Seve Ballesteros | |
dc.contributor.funder | Marie Curie | |
dc.contributor.funder | Knut and Alice Wallenberg Foundation | |
dc.contributor.funder | Swedish Foundation for Strategic Research | |
dc.contributor.funder | Swedish Cancer Society (Cancerfonden) | |
dc.contributor.funder | Swedish Research Council | |
dc.contributor.funder | Göran Gustafsson Foundation | |
dc.contributor.funder | Swedish Children’s Cancer Foundation | |
dc.contributor.funder | Swedish Pain Relief Foundation | |
dc.contributor.funder | Torsten and Ragnar Söderberg Foundation | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1949-2553 | es_ES |
dc.relation.publisherversion | https://doi.org/10.18632/oncotarget.19404. | es_ES |
dc.identifier.journal | Oncotarget | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación::Grupo de Tumores Cerebrales Fundación Seve-Ballesteros | es_ES |
dc.rights.accessRights | open access | es_ES |