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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

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

Authors: Hussein H. K. Abbas, Kheloud M. H. Alhamoudi, Mark D. Evans, George D. D. Jones, Steven S. Foster

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

Targeted 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.

Methods

Using 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.

Results

MTH1 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.

Conclusions

MTH1 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.
Appendix
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Literature
1.
Helleday T. Cancer phenotypic lethality, exemplified by the non-essential MTH1 enzyme being required for cancer survival. Ann Oncol. 2014;25(7):1253.CrossRefPubMed
2.
Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7.CrossRefPubMed
3.
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21.CrossRefPubMed
4.
5.
Toledo LI, Murga M, Fernandez-Capetillo O. Targeting ATR and Chk1 kinases for cancer treatment: a new model for new (and old) drugs. Mol Oncol. 2011;5(4):368–73.CrossRefPubMedPubMedCentral
6.
Puigvert JC, Sanjiv K, Helleday T. Targeting DNA repair, DNA metabolism and replication stress as anti-cancer strategies. FEBS J. 2016;283(2):232–45.CrossRefPubMed
7.
Kumar B, Koul S, Khandrika L, Meacham RB, Koul HK. Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res. 2008;68(6):1777–85.CrossRefPubMed
8.
Dizdaroglu M, Jaruga P. Mechanisms of free radical-induced damage to DNA. Free Radic Res. 2012;46(4):382–419.CrossRefPubMed
9.
Topal MD, Baker MS. DNA precursor pool: a significant target for N-methyl-N-nitrosourea in C3H/10T1/2 clone 8 cells. Proc Natl Acad Sci U S A. 1982;79(7):2211–5.CrossRefPubMedPubMedCentral
10.
Shibutani S, Takeshita M, Grollman AP. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature. 1991;349(6308):431–4.CrossRefPubMed
11.
Rai P, Onder TT, Young JJ, McFaline JL, Pang B, Dedon PC, et al. Continuous elimination of oxidized nucleotides is necessary to prevent rapid onset of cellular senescence. Proc Natl Acad Sci U S A. 2009;106(1):169–74.CrossRefPubMed
12.
Olinski R, Gackowski D, Rozalski R, Foksinski M, Bialkowski K. Oxidative DNA damage in cancer patients: a cause or a consequence of the disease development? Mutat Res Fund Mol Mech Mut. 2003;531(1):177–90.CrossRef
13.
Sakumi K, Furuichi M, Tsuzuki T, Kakuma T, Kawabata S, Maki H, et al. Cloning and expression of cDNA for a human enzyme that hydrolyzes 8-oxo-dGTP, a mutagenic substrate for DNA synthesis. J Biol Chem. 1993;268(31):23524–30.PubMed
14.
Fujikawa K, Kamiya H, Yakushiji H, Nakabeppu Y, Kasai H. Human MTH1 protein hydrolyzes the oxidized ribonucleotide, 2-hydroxy-ATP. Nucleic Acids Res. 2001;29(2):449–54.CrossRefPubMedPubMedCentral
15.
Nissink JWM, Bista M, Breed J, Carter N, Embrey K, Read J, et al. MTH1 substrate recognition—an example of specific promiscuity. PLoS One. 2016;11(3):e0151154.CrossRefPubMedPubMedCentral
16.
van Loon B, Markkanen E, Hübscher U. Oxygen as a friend and enemy: how to combat the mutational potential of 8-oxo-guanine. DNA Repair. 2010;9(6):604–16.CrossRefPubMed
17.
Kennedy CH, Cueto R, Belinsky SA, Lechner JF, Pryor WA. Overexpression of hMTH1 mRNA: a molecular marker of oxidative stress in lung cancer cells. FEBS Lett. 1998;429(1):17–20.CrossRefPubMed
18.
Kennedy CH, Pass HI, Mitchell JB. Expression of human MutT homologue (hMTH1) protein in primary non-small-cell lung carcinomas and histologically normal surrounding tissue. Free Radic Biol Med. 2003;34(11):1447–57.CrossRefPubMed
19.
Okamoto K, Toyokuni S, Kim WJ, Ogawa O, Kakehi Y, Arao S, et al. Overexpression of human mutT homologue gene messenger RNA in renal-cell carcinoma: evidence of persistent oxidative stress in cancer. Int J Cancer. 1996;65(4):437.CrossRefPubMed
20.
Wani G, Milo GE, D'Ambrosio SM. Enhanced expression of the 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase gene in human breast tumor cells. Cancer Lett. 1998;125(1–2):123–30.CrossRefPubMed
21.
Tu Y, Wang Z, Wang X, Yang H, Zhang P, Johnson M, et al. Birth of MTH1 as a therapeutic target for glioblastoma: MTH1 is indispensable for gliomatumorigenesis. Am J Transl Res. 2016;8(6):2803–11.PubMedPubMedCentral
22.
Gad H, Koolmeister T, Jemth AS, Eshtad S, Jacques SA, Strom CE, et al. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature. 2014;508(7495):215–21.CrossRefPubMed
23.
Speina E, Arczewska KD, Gackowski D, Zielinska M, Siomek A, Kowalewski J, et al. Contribution of hMTH1 to the maintenance of 8-oxoguanine levels in lung DNA of non-small-cell lung cancer patients. J Natl Cancer Inst. 2005;97(5):384–95.CrossRefPubMed
24.
Rai P, Young JJ, Burton DGA, Giribaldi MG, Onder TT, Weinberg RA. Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence. Oncogene. 2011;30(12):1489–96.CrossRefPubMed
25.
Patel A, Burton DGA, Halvorsen K, Balkan W, Reiner T, Perez-Stable C, et al. MutT homolog 1 (MTH1) maintains multiple KRAS-driven pro-malignant pathways. Oncogene. 2015;34(20):2586–96.CrossRefPubMed
26.
Giribaldi MG, Munoz A, Halvorsen K, Patel A, Rai P. MTH1 expression is required for effective transformation by oncogenic HRAS. Oncotarget. 2015;6(13):11519–29.CrossRefPubMedPubMedCentral
27.
Huber KV, Salah E, Radic B, Gridling M, Elkins JM, Stukalov A, et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature. 2014;508(7495):222–7.CrossRefPubMedPubMedCentral
28.
Nakabeppu Y. Cellular levels of 8-oxoguanine in either DNA or the nucleotide pool play pivotal roles in carcinogenesis and survival of cancer cells. Int J Mol Sci. 2014;15(7):12543–57.CrossRefPubMedPubMedCentral
29.
Kettle JG, Alwan H, Bista M, Breed J, Davies NL, Eckersley K, et al. Potent and selective inhibitors of MTH1 probe its role in cancer cell survival. J Med Chem. 2016;59(6):2346–61.CrossRefPubMed
30.
Kawamura T, Kawatani M, Muroi M, Kondoh Y, Futamura Y, Aono H, et al. Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival. Sci Rep. 2016;6:26521.CrossRefPubMedPubMedCentral
31.
Petrocchi A, Leo E, Reyna NJ, Hamilton MM, Shi X, Parker CA, et al. Identification of potent and selective MTH1 inhibitors. Bioorg Med Chem Lett. 2016;26(6):1503–7.CrossRefPubMed
32.
Samaranayake GJ, Huynh M, Rai P. MTH1 as a chemotherapeutic target: the elephant in the room. Cancers (Basel). 2017;9(5):47.CrossRef
33.
Coleman MP, Forman D, Bryant H, Butler J, Rachet B, Maringe C, et al. Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995-2007 (the international Cancer benchmarking partnership): an analysis of population-based cancer registry data. Lancet. 2011;377(9760):127–38.CrossRefPubMedPubMedCentral
34.
Haslett K, Pottgen C, Stuschke M, Faivre-Finn C. Hyperfractionated and accelerated radiotherapy in non-small cell lung cancer. J Thorac Dis. 2014;6(4):328–35.PubMedPubMedCentral
35.
36.
Singh NP, McCoy MT, Tice RR, Schneider EL. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res. 1988;175(1):184–91.CrossRefPubMed
37.
Kelts JL, Cali JJ, Duellman SJ, Shultz J. Altered cytotoxicity of ROS-inducing compounds by sodium pyruvate in cell culture medium depends on the location of ROS generation. Spring. 2015;4:269.CrossRef
38.
Warpman Berglund U, Sanjiv K, Gad H, Kalderen C, Koolmeister T, Pham T, et al. Validation and development of MTH1 inhibitors for treatment of cancer. Ann Oncol. 2016;27(12):2275–83.CrossRefPubMed
39.
Carter M, Jemth AS, Hagenkort A, Page BD, Gustafsson R, Griese JJ, et al. Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2. Nat Commun. 2015;6:7871.CrossRefPubMedPubMedCentral
40.
Oka S, Ohno M, Tsuchimoto D, Sakumi K, Furuichi M, Nakabeppu Y. Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs. EMBO J. 2008;27(2):421–32.CrossRefPubMedPubMedCentral
41.
Yoshimura D, Salumi K, Ohio M, Sakai Y, Furuichi M, Iowa S, et al. An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress. J Biol Chem. 2003;278(39):37965–73.CrossRefPubMed
42.
Haghdoost S, Czene S, Näslund I, Skog S, Harms-Ringdahl M. Extracellular 8-oxo-dG as a sensitive parameter for oxidative stress in vivo and in vitro. Free Radic Res. 2005;39(2):153–62.CrossRefPubMed
43.
Ke Y, Lv Z, Yang X, Zhang J, Huang J, Wu S, et al. Compensatory effects of hOGG1 for hMTH1 in oxidative DNA damage caused by hydrogen peroxide. Toxicol Lett. 2014;230(1):62–8.CrossRefPubMed
44.
45.
Britton S, Salles B, Calsou P. C-MYC protein is degraded in response to UV irradiation. Cell Cycle. 2008;7(1):63–70.CrossRefPubMed
46.
Conklin KA. Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integr Cancer Ther. 2004;3(4):294–300.CrossRefPubMed
47.
Donadelli M, Costanzo C, Beghelli S, Scupoli MT, Dandrea M, Bonora A, et al. Synergistic inhibition of pancreatic adenocarcinoma cell growth by trichostatin a and gemcitabine. Biochim Biophys Acta. 2007;1773(7):1095–106.CrossRefPubMed
48.
Oguri T, Achiwa H, Sato S, Bessho Y, Takano Y, Miyazaki M, et al. The determinants of sensitivity and acquired resistance to gemcitabine differ in non-small cell lung cancer: a role of ABCC5 in gemcitabine sensitivity. Mol Cancer Ther. 2006;5(7):1800–6.CrossRefPubMed
49.
Bepler G, Kusmartseva I, Sharma S, Gautam A, Cantor A, Sharma A, et al. RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol. 2006;24(29):4731–7.CrossRefPubMed
50.
Toschi L, Cappuzzo F. Gemcitabine for the treatment of advanced nonsmall cell lung cancer. Onco Targets Ther. 2009;2:209–17.PubMedPubMedCentral
51.
52.
Un F. G1 arrest induction represents a critical determinant for cisplatin cytotoxicity in G1 checkpoint-retaining human cancers. Anti-Cancer Drugs. 2007;18(4):411–7.CrossRefPubMed
53.
Itoh T, Terazawa R, Kojima K, Nakane K, Deguchi T, Ando M, et al. Cisplatin induces production of reactive oxygen species via NADPH oxidase activation in human prostate cancer cells. Free Radic Res. 2011;45(9):1033–9.CrossRefPubMed
54.
Casares C, Ramirez-Camacho R, Trinidad A, Roldan A, Jorge E, Garcia-Berrocal JR. Reactive oxygen species in apoptosis induced by cisplatin: review of physiopathological mechanisms in animal models. Eur Arch Otorhinolaryngol. 2012;269(12):2455–9.CrossRefPubMed
55.
Marullo R, Werner E, Degtyareva N, Moore B, Altavilla G, Ramalingam SS, et al. Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PLoS One. 2013;8(11):e81162.CrossRefPubMedPubMedCentral
56.
Wikman H, Risch A, Klimek F, Schmezer P, Spiegelhalder B, Dienemann H, et al. hOGG1 polymorphism and loss of heterozygosity (LOH): significance for lung cancer susceptibility in a caucasian population. Int J Cancer. 2000;88(6):932–7.CrossRefPubMed
57.
Mambo E, Chatterjee A, de Souza-Pinto NC, Mayard S, Hogue BA, Hoque MO, Dizdaroglu M, et al. Oxidized guanine lesions and hOgg1 activity in lung cancer. Oncogene. 2005;24(28):4496–508.CrossRefPubMed
58.
Long LH, Halliwell B. Artefacts in cell culture: pyruvate as a scavenger of hydrogen peroxide generated by ascorbate or epigallocatechin gallate in cell culture media. Biochem Biophys Res Commun. 2009;388(4):700–4.CrossRefPubMed
59.
Fotouhi A, Skiold S, Shakeri-Manesh S, Osterman-Golkar S, Wojcik A, Jenssen D, et al. 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. Mutat Res. 2011;715(1–2):13–8.CrossRefPubMed
60.
Russo MT, Blasi MF, Chiera F, Fortini P, Degan P, Macpherson P, et al. The oxidized deoxynucleoside triphosphate pool is a significant contributor to genetic instability in mismatch repair-deficient cells. Mol Cell Biol. 2004;24(1):465–74.CrossRefPubMedPubMedCentral
61.
Mazouzi A, Velimezi G, Loizou JI. DNA replication stress: causes, resolution and disease. Exp Cell Res. 2014;329(1):85–93.CrossRefPubMed
62.
63.
Strumberg D, Pilon AA, Smith M, Hickey R, Malkas L, Pommier Y. Conversion of topoisomerase I cleavage complexes on the leading strand of ribosomal DNA into 59-phosphorylated DNA double-strand breaks by replication runoff. Mol Cell Biol. 2000;20(11):3977–87.CrossRefPubMedPubMedCentral
64.
Hanada K, Budzowska M, Davies SL, van Drunen E, Onizawa H, Beverloo HB, et al. The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks. Nat Struct Mol Biol. 2007;14(11):1096–104.CrossRefPubMed
65.
Regairaz M, Zhang Y, Fu H, Agama KK, Tata N, Agrawal S, et al. Mus81-mediated DNA cleavage resolves replication forks stalled by topoisomerase I-DNA complexes. J Cell Biol. 2011;195(5):739–49.CrossRefPubMedPubMedCentral
66.
Lee JA, Carvalho CMB, Lupski JR. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell. 2007;131(7):1235–47.CrossRefPubMed
67.
Zhang F, Towne CF, Lupski JR, Connolly AM, Khajavi M, Batish SD. The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nature Genet. 2009;41(7):849–53.CrossRefPubMedPubMedCentral
68.
Hastings PJ, Ira G, Lupski JR. A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet. 2009;5(1):e1000327.CrossRefPubMedPubMedCentral
69.
Liu P, Erez A, Nagamani S, Dhar S, Kołodziejska K, Dharmadhikari A, et al. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell. 2011;146(6):889–903.CrossRefPubMedPubMedCentral
70.
71.
72.
Zhang Y, Hunter T. Roles of Chk1 in cell biology and cancer therapy. Int J Cancer. 2014;134(5):1013–23.CrossRefPubMed
73.
Wang JY, Jin L, Yan XG, Sherwin S, Farrelly M, Zhang YY, et al. Reactive oxygen species dictate the apoptotic response of melanoma cells to TH588. J Invest Dermatol. 2016;136(11):2277–86.CrossRefPubMed
Metadata
Title
MTH1 deficiency selectively increases non-cytotoxic oxidative DNA damage in lung cancer cells: more bad news than good?
Authors
Hussein H. K. Abbas
Kheloud M. H. Alhamoudi
Mark D. Evans
George D. D. Jones
Steven S. Foster
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4332-7

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