Addiction to MTH1 protein results in intense expression in human breast cancer tissue as measured by liquid chromatography-isotope-dilution tandem mass spectrometry

Coşkun, Erdem; Jemth, Ann-Sofie; Loseva, Olga; Scanlan, Leona D.; Tona, Alessandro; Lowenthal, Mark S.; Helleday, Thomas; Dizdaroğlu, Miral

doi:10.1016/j.dnarep.2015.05.008

Cited by 30 publications

(39 citation statements)

References 41 publications

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“…MTH1 protein expression is found to be higher in tumor tissue relative to matched normal tissue [20,21,22] suggesting that the tumors have a greater reliance on MTH1 function, presumably due to their higher levels of oxidative stress. In non-small cell lung carcinoma (NSCLC), a tumor type characterized by dysfunctional BER and low levels of OGG1 [23,24], MTH1 has been reported as the major determinant of genomic 8-oxoGua levels and is associated with low levels of G -> T transversions [25], a signature 8-oxoGua mutation due to its enhanced ability to pair with adenine.…”

Section: A Functional Role For Mth1 In Tumor Biologymentioning

confidence: 99%

MTH1 as a Chemotherapeutic Target: The Elephant in the Room

Samaranayake

Huynh

Rai

2017

Cancers

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Many tumors sustain elevated levels of reactive oxygen species (ROS), which drive oncogenic signaling. However, ROS can also trigger anti-tumor responses, such as cell death or senescence, through induction of oxidative stress and concomitant DNA damage. To circumvent the adverse consequences of elevated ROS levels, many tumors develop adaptive responses, such as enhanced redox-protective or oxidatively-generated damage repair pathways. Targeting these enhanced oxidative stress-protective mechanisms is likely to be both therapeutically effective and highly specific to cancer, as normal cells are less reliant on such mechanisms. In this review, we discuss one such stress-protective protein human MutT Homolog1 (MTH1), an enzyme that eliminates 8-oxo-7,8-dihydro-2’-deoxyguanosine triphosphate (8-oxodGTP) through its pyrophosphatase activity, and is found to be elevated in many cancers. Our studies, and subsequently those of others, identified MTH1 inhibition as an effective tumor-suppressive strategy. However, recent studies with the first wave of MTH1 inhibitors have produced conflicting results regarding their cytotoxicity in cancer cells and have led to questions regarding the validity of MTH1 as a chemotherapeutic target. To address the proverbial "elephant in the room" as to whether MTH1 is a bona fide chemotherapeutic target, we provide an overview of MTH1 function in the context of tumor biology, summarize the current literature on MTH1 inhibitors, and discuss the molecular contexts likely required for its efficacy as a therapeutic target.

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Section: A Functional Role For Mth1 In Tumor Biologymentioning

confidence: 99%

MTH1 as a Chemotherapeutic Target: The Elephant in the Room

Samaranayake

Huynh

Rai

2017

Cancers

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“…Fractions containing 15 N-hMTH1 protein were pooled and stored in 20 mmol/L HEPES, 225 mmol/L NaCl, 10% glycerol, and 1 mmol/L Tris (2-carboxyethyl)-phosphine hydrochloride at −80° C The purity of the isolated 15 N-hMTH1 was checked using SDS–PAGE with Coomassie staining. Figure 5 illustrates the SDS–PAGE analysis of 15 N-hMTH1 along with hMTH1 and protein standards, indicating high purity of both proteins (Coskun et al, 2015). …”

Section: Production and Purification Of 15n-hmth1mentioning

confidence: 99%

“…The molecular mass of 15 N-hMTH1 was measured using a high-resolution QToF mass spectrometer coupled to an HPLC system (Coskun et al, 2015). Without the N-terminal Met, the calculated MH + of 15 N-hMTH1 amounts to 20229.8 Da.…”

Section: Mass Spectrometric Analysis Of 15n-labeled Proteinsmentioning

confidence: 99%

“…The shift in the mass of (M+2H) 2+ was also in agreement with the mass difference of 14 Da. To obtain product ion spectra, optimum collision energies using (M+2H) 2+ ions as the precursor ions were measured (Coskun et al, 2015; Reddy et al, 2013). These were in agreement with previously determined collision energies of peptides with similar masses (Kinter & Sherman, 2000).…”

Section: Applications To the Measurement Of Dna Repair Proteinsmentioning

confidence: 99%

“…The application of this technique would be essential for positive identification and accurate quantification of DNA repair proteins in human tissues using proper internal standards. Our laboratory has recently developed methodologies and stable isotope-labeled standards for the measurements of DNA repair proteins using liquid chromatography–tandem mass spectrometry (LC-MS/MS) with isotope dilution (Coskun et al, 2015; Dizdaroglu, Reddy, & Jaruga, 2011; Kirkali et al, 2013; Reddy, Jaruga, Nelson, Lowenthal, & Dizdaroglu, 2011; Reddy et al, 2013). Stable isotope-labeled analogs of DNA repair proteins, which are to be used as internal standards, were produced, purified, and characterized.…”

Section: Introductionmentioning

confidence: 99%

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Production, Purification, and Characterization of 15N-Labeled DNA Repair Proteins as Internal Standards for Mass Spectrometric Measurements

Reddy

Nelson

Lowenthal

et al. 2016

Methods in Enzymology

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Oxidatively induced DNA damage is caused in living organisms by a variety of damaging agents, resulting in the formation of a multiplicity of lesions, which are mutagenic and cytotoxic. Unless repaired by DNA repair mechanisms before DNA replication, DNA lesions can lead to genomic instability, which is one of the hallmarks of cancer. Oxidatively induced DNA damage is mainly repaired by base excision repair pathway with the involvement of a plethora of proteins. Cancer tissues develop greater DNA repair capacity than normal tissues by overexpressing DNA repair proteins. Increased DNA repair in tumors that removes DNA lesions generated by therapeutic agents before they became toxic is a major mechanism in the development of therapy resistance. Evidence suggests that DNA repair capacity may be a predictive biomarker of patient response. Thus, knowledge of DNA–protein expressions in disease-free and cancerous tissues may help predict and guide development of treatments and yield the best therapeutic response. Our laboratory has developed methodologies that use mass spectrometry with isotope dilution for the measurement of expression of DNA repair proteins in human tissues and cultured cells. For this purpose, full-length 15N-labeled analogs of a number of human DNA repair proteins have been produced and purified to be used as internal standards for positive identification and accurate quantification. This chapter describes in detail the protocols of this work. The use of 15N-labeled proteins as internal standards for the measurement of several DNA repair proteins in vivo is also presented.

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OGG1 contributes to hepatocellular carcinoma by promoting cell cycle‐related protein expression and enhancing DNA oxidative damage repair in tumor cells

Zhang

Jiang

et al. 2022

Clinical Laboratory Analysis

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Hepatocellular carcinoma (HCC, LIHC) is a kind of primary liver cancer with high mortality. 1 Genetic and epigenetic changes, chronic hepatitis B, hepatitis C virus infection, aflatoxin exposure, smoking, obesity, and diabetes are the main risk factors for HCC. 2 In recent years, many studies focused on the molecular pathogenesis of HCC and found a series of genetic and epigenetic events that promote the tumorigenesis and development of HCC. 3 Oxidative stress is usually increased in HCC, resulting in the increase of reactive oxygen species (ROS), then resulting in DNA damage, affecting the regulation of cell proliferation-related pathways, thus promoting the tumorigenesis and development of HCC. 4 The repair methods of DNA damage include mismatch repair, excision repair,

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Addiction to MTH1 protein results in intense expression in human breast cancer tissue as measured by liquid chromatography-isotope-dilution tandem mass spectrometry

Cited by 30 publications

References 41 publications

MTH1 as a Chemotherapeutic Target: The Elephant in the Room

MTH1 as a Chemotherapeutic Target: The Elephant in the Room

Production, Purification, and Characterization of 15N-Labeled DNA Repair Proteins as Internal Standards for Mass Spectrometric Measurements

OGG1 contributes to hepatocellular carcinoma by promoting cell cycle‐related protein expression and enhancing DNA oxidative damage repair in tumor cells

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