2026-08-29T13:16:46Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/73602024-11-29T16:21:13Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Pudelko, Linda
author
Rouhi, Pegah
author
Sanjiv, Kumar
author
Gad, Helge
author
Kalderén, Christina
author
Höglund, Andreas
author
Squatrito, Massimo
author
Schuhmacher, Alberto J
author
Edwards, Steven
author
Hägerstrand, Daniel
author
Berglund, Ulrika Warpman
author
Helleday, Thomas
author
Bräutigam, Lars
funder
Fundación Seve Ballesteros
funder
Marie Curie
funder
Knut and Alice Wallenberg Foundation
funder
Swedish Foundation for Strategic Research
funder
Swedish Cancer Society (Cancerfonden)
funder
Swedish Research Council
funder
Göran Gustafsson Foundation
funder
Swedish Children’s Cancer Foundation
funder
Swedish Pain Relief Foundation
funder
Torsten and Ragnar Söderberg Foundation
2019-03-20T13:21:33Z
2019-03-20T13:21:33Z
2017-10-17
Oncotarget. 2017;8(49):84671-84684.
10.18632/oncotarget.19404
1949-2553
1949-2553
Oncotarget
29156675
http://hdl.handle.net/20.500.12105/7360
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.
eng
DNA damage
MTH1
Nudt1
Cancer stem cells
Glioblastoma multiforme
Glioblastoma and glioblastoma stem cells are dependent on functional MTH1
journal article
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