2026-08-29T13:16:56Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/73602024-11-29T16:21:13Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc 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 author 2017-10-17 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. Oncotarget. 2017;8(49):84671-84684. 10.18632/oncotarget.19404 1949-2553 1949-2553 Oncotarget 29156675 http://hdl.handle.net/20.500.12105/7360 DNA damage MTH1 Nudt1 Cancer stem cells Glioblastoma multiforme Glioblastoma and glioblastoma stem cells are dependent on functional MTH1