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Glioblastoma and glioblastoma stem cells are dependent on functional MTH1
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 49, p. 84671-84684Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Impact Journals LLC , 2017. Vol. 8, no 49, p. 84671-84684
Keywords [en]
MTH1, Nudt1, DNA damage, glioblastoma multiforme, cancer stem cells
National Category
Cancer and Oncology Cell Biology
Identifiers
URN: urn:nbn:se:kth:diva-217187DOI: 10.18632/oncotarget.19404ISI: 000413077800020Scopus ID: 2-s2.0-85031491062OAI: oai:DiVA.org:kth-217187DiVA, id: diva2:1154647
Funder
Knut and Alice Wallenberg Foundation, KAW2014.273Swedish Foundation for Strategic Research , RB13-0224Swedish Cancer SocietySwedish Research Council, 2015-00162Swedish Childhood Cancer FoundationTorsten Söderbergs stiftelseScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20171103

Available from: 2017-11-03 Created: 2017-11-03 Last updated: 2017-11-29Bibliographically approved

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