Priority Research Papers:
Glioblastoma and glioblastoma stem cells are dependent on functional MTH1
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Linda Pudelko1, Pegah Rouhi1,5, Kumar Sanjiv1, Helge Gad1, Christina Kalderén1, Andreas Höglund1, Massimo Squatrito2, Alberto J. Schuhmacher2, Steven Edwards3, Daniel Hägerstrand4, Ulrika Warpman Berglund1, Thomas Helleday1 and Lars Bräutigam1
1 Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet, Stockholm, Sweden
2 Cancer Cell Biology Programme, Seve Ballesteros Foundation Brain Tumor Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, Spain
3 Department of Applied Physics, Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden
4 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
5 Department of Oncology, Lab of Tumor Inflammation and Angiogenesis, KU Leuven, Leuven, Belgium
Lars Bräutigam, email:
Thomas Helleday, email:
Keywords: MTH1, Nudt1, DNA damage, glioblastoma multiforme, cancer stem cells
Received: April 26, 2017 Accepted: July 03, 2017 Published: July 20, 2017
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.
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