Reduction of 8-oxodGTP in the nucleotide pool by hMTH1 leads to reduction in mutations in the human lymphoblastoid cell line TK6 exposed to UVA

Fotouhi, Asal; Skiöld, Sara; Shakeri-Manesh, Sara; Osterman-Golkar, Siv; Wójcik, Andrzej; Jenssen, Dag; Harms‐Ringdahl, Mats; Haghdoost, Siamak

doi:10.1016/j.mrfmmm.2011.07.005

Cited by 15 publications

(5 citation statements)

References 41 publications

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“…Instead, given that we show that MTH1 deficiency in NSCLC cells induces non-cytotoxic DNA oxidation and DDR alterations, we propose that treating NSCLC patients with MTH1 inhibitors could actually provide an environment for further mutation accumulation to drive cancer heterogeneity and evolution. In accordance with this proposition, MTH1-knockdown in human B lymphoblastoid cells induces a higher mutation rate but not cell death after UVA-induced oxidative stress [ 59 ], while MTH1 overexpression repressed the DNA-replication-dependent mutator phenotype in mismatch-repair-defective colorectal cancer cells [ 60 ].…”

Section: Discussionmentioning

confidence: 92%

MTH1 deficiency selectively increases non-cytotoxic oxidative DNA damage in lung cancer cells: more bad news than good?

et al. 2018

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BackgroundTargeted therapies are based on exploiting cancer-cell-specific genetic features or phenotypic traits to selectively kill cancer cells while leaving normal cells unaffected. Oxidative stress is a cancer hallmark phenotype. Given that free nucleotide pools are particularly vulnerable to oxidation, the nucleotide pool sanitising enzyme, MTH1, is potentially conditionally essential in cancer cells. However, findings from previous MTH1 studies have been contradictory, meaning the relevance of MTH1 in cancer is still to be determined. Here we ascertained the role of MTH1 specifically in lung cancer cell maintenance, and the potential of MTH1 inhibition as a targeted therapy strategy to improve lung cancer treatments.MethodsUsing siRNA-mediated knockdown or small-molecule inhibition, we tested the genotoxic and cytotoxic effects of MTH1 deficiency on H23 (p53-mutated), H522 (p53-mutated) and A549 (wildtype p53) non-small cell lung cancer cell lines relative to normal MRC-5 lung fibroblasts. We also assessed if MTH1 inhibition augments current therapies.ResultsMTH1 knockdown increased levels of oxidatively damaged DNA and DNA damage signaling alterations in all lung cancer cell lines but not normal fibroblasts, despite no detectable differences in reactive oxygen species levels between any cell lines. Furthermore, MTH1 knockdown reduced H23 cell proliferation. However, unexpectedly, it did not induce apoptosis in any cell line or enhance the effects of gemcitabine, cisplatin or radiation in combination treatments. Contrastingly, TH287 and TH588 MTH1 inhibitors induced apoptosis in H23 and H522 cells, but only increased oxidative DNA damage levels in H23, indicating that they kill cells independently of DNA oxidation and seemingly via MTH1-distinct mechanisms.ConclusionsMTH1 has a NSCLC-specific p53-independent role for suppressing DNA oxidation and genomic instability, though surprisingly the basis of this may not be reactive-oxygen-species-associated oxidative stress. Despite this, overall our cell viability data indicates that targeting MTH1 will likely not be an across-the-board effective NSCLC therapeutic strategy; rather it induces non-cytotoxic DNA damage that could promote cancer heterogeneity and evolution.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4332-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 92%

MTH1 deficiency selectively increases non-cytotoxic oxidative DNA damage in lung cancer cells: more bad news than good?

et al. 2018

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“…The relevance of extracellular 8-oxo-dG induction in irradiated cells was previously shown [57]. By knocking down hMTH1, we have previously shown that the extracellular 8-oxo-dG originates from the reaction between reactive oxygen species and cytoplasmic contents of dGTP [57], which lead to the formation of 8-oxo-dGTP, a mutagenic nucleotide, since during its replication, 8-oxo-dGTP can be incorporated into the DNA and generate transversion due to mispairing with adenine [67]. MTH1 converts 8-oxo-dGTP to 8-oxo-dGMP, which is released from the cells as 8-oxo-dG.…”

Section: Discussionmentioning

confidence: 94%

Targeting NRF2, Regulator of Antioxidant System, to Sensitize Glioblastoma Neurosphere Cells to Radiation-Induced Oxidative Stress

Godoy

Khavari

Rizzo

et al. 2020

Oxidative Medicine and Cellular Longevity

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The presence of glioma stem cells (GSCs), which are enriched in neurospheres, may be connected to the radioresistance of glioblastoma (GBM) due to their enhanced antioxidant defense and elevated DNA repair capacity. The aim was to evaluate the responses to different radiation qualities and to reduce radioresistance of U87MG cells, a GBM cell line. U87MG cells were cultured in a 3D model and irradiated with low (24 mGy/h) and high (0.39 Gy/min) dose rates of low LET gamma and high LET carbon ions (1-2 Gy/min). Thereafter, expression of proteins related to oxidative stress response, extracellular 8-oxo-dG, and neurospheres were determined. LD50 for carbon ions was significantly lower compared to LD50 of high and low dose rate gamma radiation. A significantly higher level of 8-oxo-dG was detected in the media of cells exposed to a low dose rate as compared to a high dose rate of gamma or carbon ions. A downregulation of oxidative stress proteins was also observed (NRF2, hMTH1, and SOD1). The NRF2 gene was knocked down by CRISPR/Cas9 in neurosphere cells, resulting in less self-renewal, more differentiated cells, and less proliferation capacity after irradiation with low and high dose rate gamma rays. Overall, U87MG glioma neurospheres presented differential responses to distinct radiation qualities and NRF2 plays an important role in cellular sensitivity to radiation.

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“…2). Oxidized guanine (8-oxoGua), frequently measured as 8-oxo-7,8-dihydro-2 0 -deoxyguanosine (8-oxodG), is one of the most abundant oxidative stress-induced lesion in DNA, resulting from direct oxidation or from possibly DNA polymerase-dependent incorporation of 8-oxodGTP from the nucleotide pool (3)(4)(5). 8-OxoGua in DNA causes G-T transversion mutations upon replication of DNA (6), unless excised by oxoguanine DNA glycosylase (OGG1; ref.…”

Section: Introductionmentioning

confidence: 99%

Association between 8-oxo-7,8-dihydro-2′-deoxyguanosine Excretion and Risk of Postmenopausal Breast Cancer: Nested Case–Control Study

Loft

Olsen

Möller

et al. 2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Reduction of 8-oxodGTP in the nucleotide pool by hMTH1 leads to reduction in mutations in the human lymphoblastoid cell line TK6 exposed to UVA

Cited by 15 publications

References 41 publications

MTH1 deficiency selectively increases non-cytotoxic oxidative DNA damage in lung cancer cells: more bad news than good?

MTH1 deficiency selectively increases non-cytotoxic oxidative DNA damage in lung cancer cells: more bad news than good?

Targeting NRF2, Regulator of Antioxidant System, to Sensitize Glioblastoma Neurosphere Cells to Radiation-Induced Oxidative Stress

Association between 8-oxo-7,8-dihydro-2′-deoxyguanosine Excretion and Risk of Postmenopausal Breast Cancer: Nested Case–Control Study

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