Glioblastoma and glioblastoma stem cells are dependent on functional MTH1.

Pudelko L, Rouhi P, Sanjiv K, Gad H, Kalderén C, Höglund A, Squatrito M, Schuhmacher AJ, Edwards S, Hägerstrand D, Berglund UW, Helleday T, Bräutigam L

Oncotarget 8 (49) 84671-84684 [2017-10-17; online 2017-07-20]

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

Affiliated researcher

PubMed 29156675

DOI 10.18632/oncotarget.19404

Crossref 10.18632/oncotarget.19404

pii: 19404
pmc: PMC5689565

Publications 9.5.0