Article
Inhibition of MutT homolog 1 (MTH1) in glioblastoma multiforme results in impaired cell migration and tumor growth
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Authors
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Marco Timmer
- Allgemeine Neurochirurgie, Uniklinik Köln, Klinikum der Universität zu Köln, Zentrum für Neurochirurgie, Klinik für Allgemeine Neurochirurgie, Köln, Deutschland
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Sara Kannampuzha
- Köln, Deutschland
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Gabriele Röhn
- Klinikum der Universität zu Köln, Zentrum für Neurochirurgie, Labor für Neuroonkologie und experimentelle Neurochirurgie, Köln, Deutschland
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Boris Krischek
- Zentrum für Neurochirurgie, Klinik für Allgemeine Neurochirurgie, Köln, Deutschland
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Roland Goldbrunner
- Klinikum der Universität zu Köln, Zentrum für Neurochirurgie, Klinik für Allgemeine Neurochirurgie, Köln, Deutschland
| Published: | June 9, 2017 |
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Outline
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OBJECTIVE: MutT homolog1 (MTH1) is required for survival of cancer cells. These have irregular redox formations resulting in the production of reactive oxygen species which damage the deoxynucleoside triphosphate pool and subsequent the DNA. MTH1 plays a crucial role by inhibiting the incorporation of oxidized bases into the DNA that avoid apoptosis of cancer cells. Our aim was to analyze the pathophysiological role of MTH1 in glioma.
METHODS: MTH1 expression was analyzed in human glioma specimens by quantitative RT-PCR, immunohistochemistry and Western Blot. U87 proliferation, cell migration in vitro and tumor growth in an orthotopic rat model was monitored after knock-down of MTH1 by siRNA or inhibition by crizotinib. In addition, progression free- and overall survival of patients was correlated to the MTH1 level using both, own data and the TCGA dataset.
RESULTS: Higher expression of MTH1 was observed in glioblastoma than in lower grade astrocytomas and peritumoral tissue, both, on the gene and protein level. Quantitative RT-PCR resulted in a threefold MTH1 mRNA increase in GBM (6.93±1.38) compared to diffuse astrocytoma (2.35±0.27). Immunohistochemistry and Western blot analysis revealed a highly significant grade dependent upregulation of MTH1 in gliomas: control tissue 0.19±0.07; astrocytoma WHO°II 1.42±0.74; astrocytoma WHO°III 2.20±0.55; glioblastoma 5.97±2.68 (p<0.001). MTH1 siRNA transfected U87 cells showed slower migration compared to control U87 cells. Furthermore, treatment with crizotinib, an inhibitor of MTH1, also lowered cell migration (gap distance difference after 24h 994µm±49; p<0.01). In rats, tumor growth was significantly impaired in MTH1 siRNA U87 grafts. Additionally, the data indicate an inverse correlation between the progression free- and overall survival of patients and the expression level of MTH1 (p<0.05).
CONCLUSION: These results show that MTH1 plays an essential role in both, malignization of glioma and disease progression in recurrent glioblastoma. Moreover, the MTH1 level in patients seems to influence tumor growth and patient survival and could be targeted by crizotinib indicating a putative role for potential future therapies.
