DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway

Kang, M A; So, E-Y; Simons, A L; Spitz, D R; Ouchi, T

doi:10.1038/cddis.2011.134

Cited by 311Redox biology and oxidative stressDNA Repair MechanismsNeutrophil, Myeloperoxidase and Oxidative Mechanisms

DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway

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Kang, M A, So, E-Y, Simons, A L, Spitz, D R, Ouchi, T·2012·Cell Death & Disease

DOI 10.1038/cddis.2011.134PMC PMC3270268

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Abstract

The DNA damage response (DDR) cascade and ROS (reactive oxygen species) signaling are both involved in the induction of cell death after DNA damage, but a mechanistic link between these two pathways has not been clearly elucidated. This study demonstrates that ROS induction after treatment of cells with neocarzinostatin (NCS), an ionizing radiation mimetic, is at least partly mediated by increasing histone H2AX. Increased levels of ROS and cell death induced by H2AX overexpression alone or DNA damage leading to H2AX accumulation are reduced by treating cells with the antioxidant N-Acetyl-L-Cysteine (NAC), the NADP(H) oxidase (Nox) inhibitor DPI, expression of Rac1N17, and knockdown of Nox1, but not Nox4, indicating that induction of ROS by H2AX is mediated through Nox1 and Rac1 GTPase. H2AX increases Nox1 activity partly by reducing the interaction between a Nox1 activator NOXA1 and its inhibitor 14-3-3zeta. These results point to a novel role of histone H2AX that regulates Nox1-mediated ROS generation after DNA damage.

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Increased H2AX+ signals overlap with p19+ signal around BMAds in both AD mice and old mice.
“Additionally, we observed increased H2AX+ signals, indicative of reactive oxygen species generation, DNA damage and repair48,49. The increased H2AX+ signals overlapped with p19+ signal around BMAds in both AD mice (Fig. 3i,k) and old mice (Fig. 3l,n).”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [48]
The Results section reports H2AX responses to DNA damage and ROS in cultured human cell lines, but does not address p19 signals, bone marrow adipocytes (BMAds), AD mice, or old mice. The overlap described in the quoted claim is presented as the citing authors’ own observation, not as a finding from this source. (LLM, conf=0.76)
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Background
Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson’s disease
Milanese, C., Cerri, S., Ulusoy, A., Gornati, S. V., Plat, A., Gabriels, S., Blandini, F., Di Monte, D. A., Hoeijmakers, J. H., & Mastroberardino, P. G. (2018) · Cell Death & Disease · doi:10.1038/s41419-018-0848-7 · Cited by 118 · see citing works
Switching from membrane disrupting to membrane crossing, an effective strategy in designing antibacterial polypeptide
Zhang, H., Chen, Q., Xie, J.-Y., Cong, Z.-H., Cao, C., Zhang, W.-J., Zhang, D.-H., Chen, S., Gu, J., Deng, S., et al. (2023) · Science Advances · doi:10.1126/sciadv.abn0771 · Cited by 111
Bystander effects as manifestation of intercellular communication of DNA damage and of the cellular oxidative status.
Klammer, H., Mladenov, E., Li, F., & Iliakis, G. (2015) · Cancer Letters · doi:10.1016/j.canlet.2013.12.017 · Cited by 110 · see citing works
Mitotic catastrophe and cancer drug resistance: A link that must to be broken
Denisenko, T. V., Sorokina, I. V., Gogvadze, V., & Zhivotovsky, B. (2016) · Drug Resistance Updates · doi:10.1016/j.drup.2015.11.002 · Cited by 108 · see citing works
Wee-1 Kinase Inhibition Overcomes Cisplatin Resistance Associated with High-Risk TP53 Mutations in Head and Neck Cancer through Mitotic Arrest Followed by Senescence
Osman, A., Monroe, M., Ortega-Alves, M. V., Patel, A. A., Katsonis, P., Fitzgerald, A. L., Neskey, D. M., Frederick, M., Woo, S., Caulin, C., et al. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0735-t · Cited by 108
“ROS induction is most likely caused by excessive DNA damage as it was recently shown that DNA damage induces ROS generation in several tumor cell lines (40).”
Reactive oxygen species and DNA damage response in cancer
Renaudin, X. (2021) · International review of cytology · doi:10.1016/bs.ircmb.2021.04.001 · Cited by 164 · see citing works
Redox Imbalance in the Development of Colorectal Cancer
Liu, H., Liu, X., Zhang, C., Zhu, H., Xu, Q., Bu, Y., & Lei, Y. (2017) · Journal of Cancer · doi:10.7150/jca.18735 · Cited by 106 · see citing works
“For example, study reported that H2AX could regulate Nox1-mediated ROS generation after DNA damage [42].”
Background
Hace1 controls ROS generation of vertebrate Rac1-dependent NADPH oxidase complexes
Daugaard, M., Nitsch, R., Razaghi, B., Mcdonald, L., Jarrar, A., Torrino, S., Castillo-Lluva, S., Rotblat, B., Li, L., Malliri, A., et al. (2013) · Nature Communications · doi:10.1038/ncomms3180 · Cited by 106 · see citing works
Zinc oxide nanoparticle energy band gap reduction triggers the oxidative stress resulting into autophagy-mediated apoptotic cell death
Arakha, M., Roy, J., Nayak, P. S., Mallick, B., & Jha, S. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.05.015 · Cited by 112 · see citing works
Chaetocin-induced ROS-mediated apoptosis involves ATM–YAP1 axis and JNK-dependent inhibition of glucose metabolism
Dixit, D., Ghildiyal, R., Anto, N. P., & Sen, E. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.179 · Cited by 101 · see citing works
Anti-proliferative effect of methanolic extract of Gracilaria tenuistipitata on oral cancer cells involves apoptosis, DNA damage, and oxidative stress
Yeh, C.-C., Yang, J.-I., Lee, J., Tseng, C., Chan, Y., Hseu, Y., Tang, J., Chuang, L., Huang, H., Chang, F., et al. (2012) · BMC Complementary and Alternative Medicine · doi:10.1186/1472-6882-12-142 · Cited by 106 · see citing works
“Furthermore, the DNA damage response cascade and ROS signaling pathway are two of the main pathways leading to cell death [52,53].”
Background
A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics
Ding, X., Yang, C. H., Moreira, W., Yuan, P., Periaswamy, B., de Sessions, P. F., Zhao, H., Tan, J. P. K., Lee, A. L. Z., Ong, K. X., et al. (2020) · Advanced Science · doi:10.1002/advs.202001374 · Cited by 113 · see citing works
Redox modulation of the DNA damage response
Caputo, F., Vegliante, R., & Ghibelli, L. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.07.022 · Cited by 91 · see citing works
“activity by reducing the interaction between the NADPH oxidase 1 activator NOXA1 and its inhibitor 14–3–3z [122].”
Background
Cell death induced by ozone and various non-thermal plasmas: therapeutic perspectives and limitations
Lunov, O., Zablotskii, V., Churpita, O., Chánová, E., Sykova, E., Dejneka, A., & Kubínová, Š. (2014) · Scientific Reports · doi:10.1038/srep07129 · Cited by 90 · see citing works
Short-term effects on antioxidant enzymes and long-term genotoxic and carcinogenic potential of CuO nanoparticles compared to bulk CuO and ionic copper in mussels Mytilus galloprovincialis.
Ruiz, P., Katsumiti, A., Nieto, J. A., Bori, J., Jimeno-Romero, A., Reip, P., Arostegui, I., Orbea, A., & Cajaraville, M. (2015) · Marine Environmental Research · doi:10.1016/j.marenvres.2015.07.018 · Cited by 89 · see citing works
The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene <i>Ppm1d</i> Promotes Inflammation and Non-Ischemic Heart Failure in Mice
Yura, Y., Miura-Yura, E., Katanasaka, Y., Min, K.-D., Chavkin, N., Polizio, A. H., Ogawa, H., Horitani, K., Doviak, H., Evans, M. A., et al. (2021) · Circulation Research · doi:10.1161/circresaha.121.319314 · Cited by 87 · see citing works
HPV16 E6 and E7 proteins induce a chronic oxidative stress response via NOX2 that causes genomic instability and increased susceptibility to DNA damage in head and neck cancer cells.
Marullo, R., Werner, E., Zhang, H., Chen, G., Shin, D.-M., & Doetsch, P. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv126 · Cited by 85 · see citing works
Oxidative stress and hepatic Nox proteins in chronic hepatitis C and hepatocellular carcinoma
Choi, J., Corder, N. L. B., Koduru, B., & Wang, Y. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.04.020 · Cited by 86 · see citing works
Reciprocal activation between MMP-8 and TGF-β1 stimulates EMT and malignant progression of hepatocellular carcinoma.
Qin, G.-H., Luo, M., Chen, J., Dang, Y.-W., Chen, G., Li, L., Zeng, J., Lu, Y., & Yang, J. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.02.001 · Cited by 83 · see citing works
Disrupted BRCA1-PALB2 Interaction Induces Tumor Immunosuppression and T-Lymphocyte Infiltration in Hepatocellular Carcinoma Through cGAS-STING Pathway
Ma, H.-J., Kang, Z.-H., Foo, T., Shen, Z.-Y., & Xia, B. (2022) · Hepatology · doi:10.1002/hep.32335 · Cited by 82 · see citing works
“DNA damage resulting from various sources has been shown to increase intracellular levels of ROS through γH2AX‐mediated activation of the Nox1‐Rac1 complex.[37] In turn, ROS has been reported to directly induce DNA damage through oxidizing nucleoside bases, potentially leading to G‐T or G‐A transversions.”
Background
Genotoxicity analysis of cerium oxide micro and nanoparticles in Wistar rats after 28 days of repeated oral administration
Kumari, M., Kumari, S. I., & Grover, P. (2014) · Mutagenesis · doi:10.1093/mutage/geu038 · Cited by 78 · see citing works
“Likewise, H2AX-Nox1/Rac1 pathway was reported as the possible mechanism for the DNA damage and intracellular ROS signalling for the induction of cell death (57).”
Background
mTORC1 senses stresses: Coupling stress to proteostasis
Su, K.-H., & Dai, C.-K. (2017) · Bioessays · doi:10.1002/bies.201600268 · Cited by 76 · see citing works
Stimulation of mTORC1 with L-leucine Rescues Defects Associated with Roberts Syndrome
Xu, B., Lee, K. K., Zhang, L., & Gerton, J. L. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003857 · Cited by 83 · see citing works
Steroidogenic cytochrome P450 17A1 structure and function
Burris‐Hiday, S. D., & Scott, E. E. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111261 · Cited by 94 · see citing works
Poly adenosine diphosphate ribose polymerase inhibitors (PARPi) induce autophagy-mediated drug resistance in ovarian cancer cells, xenografts and PDX models
Santiago-O'Farrill, J. M., Weroha, S. J., Hou, X., Oberg, A., Heinzen, E., Maurer, M. J., Pang, L., Rask, P., Amaravadi, R., Becker, S. E., et al. (2019) · Cancer · doi:10.1002/cncr.32600 · Cited by 73 · see citing works
Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferase
Chang, K., Hsu, T.-I., Hsu, C.-C., Tsai, S., Liu, J.-J., Chou, S.-W., Liu, M.-S., Liou, J., Ko, C., Chen, K.-Y., et al. (2017) · Redox Biology · doi:10.1016/j.redox.2017.08.005 · Cited by 72 · see citing works
Up- regulation of miR-328-3p sensitizes non-small cell lung cancer to radiotherapy
Ma, W., Ma, C., Zhou, N., Li, X.-D., & Zhang, Y. (2016) · Scientific Reports · doi:10.1038/srep31651 · Cited by 86 · see citing works
Bacteria‐Targeting Photodynamic Nanoassemblies for Efficient Treatment of Multidrug‐Resistant Biofilm Infected Keratitis
Zhu, Y.-W., Wu, S., Sun, Y.-J., Zou, X., Zheng, L., Duan, S., Wang, J.-L., Yu, B.-R., Sui, R., & Xu, F.-J. (2021) · Advanced Functional Materials · doi:10.1002/adfm.202111066 · Cited by 71 · see citing works
Impairing the radioresistance of cancer cells by hydrogenated nanodiamonds.
Grall, R., Girard, H., Saad, L., Petit, T., Gesset, C., Combis-Schlumberger, M., Paget, V., Delic, J., Arnault, J., & Chevillard, S. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2015.05.034 · Cited by 71 · see citing works
“M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT ROS generation [48].”
PEDF and PEDF-derived peptide 44mer protect cardiomyocytes against hypoxia-induced apoptosis and necroptosis via anti-oxidative effect
Gao, X., Zhang, H., Zhuang, W., Yuan, G., Sun, T., Jiang, X., Zhou, Z.-X., Yuan, H., Zhang, Z.-M., & Dong, H.-Y. (2014) · Scientific Reports · doi:10.1038/srep05637 · Cited by 69 · see citing works
Mechanisms of E-Cigarette Vape-Induced Epithelial Cell Damage
Auschwitz, E., Almeda, J., & Andl, C. D. (2023) · Cells · doi:10.3390/cells12212552 · Cited by 63 · see citing works
“The DDR pathway halts the cell cycle at DNA damage sites until the damage is either repaired or the cell is subjected to apoptosis [78,93].”
Background
Remote Actuation of Apoptosis in Liver Cancer Cells via Magneto-Mechanical Modulation of Iron Oxide Nanoparticles
Lunov, O., Uzhytchak, M., Smolková, B., Lunová, M., Jirsa, M., Dempsey, N. M., Dias, A., Bonfim, M. J. C., Hof, M., Jurkiewicz, P., et al. (2019) · Cancers · doi:10.3390/cancers11121873 · Cited by 74 · see citing works
Non-volatile disinfection byproducts are far more toxic to mammalian cells than volatile byproducts
Wu, Q.-Y., Liang, Z.-F., Wang, W., Du, Y., Hu, H., Yang, L.-L., & Huang, W.-C. (2020) · Water Research · doi:10.1016/j.watres.2020.116080 · Cited by 69 · see citing works
Norcantharidin Induced DU145 Cell Apoptosis through ROS-Mediated Mitochondrial Dysfunction and Energy Depletion
Shen, B., He, P.-J., & Shao, C.-L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0084610 · Cited by 66 · see citing works
“A recent research also indicated that H2AX, a well-known specific and sensitive reporter of DNA damage could up-regulate the activity of NADP(H) oxidase (Nox), thus increasing the generation of ROS and aggravating DNA damage [35].”
Background
Identification of NCF2/p67phox as a novel p53 target gene
Italiano, D., Lena, A. M., Melino, G., & Candi, E. (2012) · Cell Cycle · doi:10.4161/cc.22853 · Cited by 74 · see citing works
Gamma rays induce DNA damage and oxidative stress associated with impaired growth and reproduction in the copepod Tigriopus japonicus.
Han, J., Won, E.-J., Lee, B.-Y., Hwang, U., Kim, I.-C., Yim, J., Leung, K., Lee, Y.-S., & Lee, J.-S. (2014) · Aquatic Toxicology · doi:10.1016/j.aquatox.2014.04.005 · Cited by 63 · see citing works
NADPH oxidase-1 plays a key role in keratinocyte responses to UV radiation and UVB-induced skin carcinogenesis
Raad, H., Serrano-Sanchez, M., Harfouche, G., Mahfouf, W., Bortolotto, D., Bergeron, V., Kasraian, Z., Dousset, L., Hosseini, M., Taieb, A., et al. (2017) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.12.027 · Cited by 62 · see citing works
Effects of Blue Light Emitting Diode Irradiation On the Proliferation, Apoptosis and Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells
Yuan, Y., Yan, G., Gong, R., Zhang, L., Liu, T.-Y., Feng, C., Du, W., Wang, Y., Yang, F., Li, Y., et al. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000480344 · Cited by 59 · see citing works
NUPR1: A Critical Regulator of the Antioxidant System
Huang, C., Santofimia-Castaño, P., & Iovanna, J. (2021) · Cancers · doi:10.3390/cancers13153670 · Cited by 58 · see citing works
“For instance, γ-H2AX, a histone that regulates ROS-mediated DNA damage through the Nox1/Rac1 pathway, was highly increased in NUPR1 knockdown cells subjected to hypoxia or glucose starvation [46,47,64].”
Background
Radiation as an In Situ Auto-Vaccination: Current Perspectives and Challenges
Goto, T. (2019) · Vaccines · doi:10.3390/vaccines7030100 · Cited by 63 · see citing works
Pharmacological Ascorbate Suppresses Growth of Gastric Cancer Cells with GLUT1 Overexpression and Enhances the Efficacy of Oxaliplatin Through Redox Modulation
Lu, Y., Wu, Q.-N., Chen, D.-L., Chen, L.-Z., Wang, Z., Ren, C., Mo, H., Ya, C., Sheng, H., Wang, Y.-N., et al. (2018) · Theranostics · doi:10.7150/thno.21745 · Cited by 65 · see citing works
“DNA damage has been shown to induce ROS generation through the H2AX/Nox1/ Rac1 pathway[21].”
Background
Potent Anticancer Activity with High Selectivity of a Chiral Palladium N-Heterocyclic Carbene Complex
Kumar, A., Naaz, A., Prakasham, A., Gangwar, M., Butcher, R., Panda, D., & Ghosh, P. (2017) · ACS Omega · doi:10.1021/acsomega.7b00688 · Cited by 58
Selenoprotein H Suppresses Cellular Senescence through Genome Maintenance and Redox Regulation
Wu, R. T. Y., Cao, L., Chen, B. P. C., & Cheng, W.-H. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.611970 · Cited by 55 · see citing works
“Similarly, both camptothecin, an inhibitor of topoisomerase I (61), and neocarzinostatin, an ionizing radiation mimicry, have been reported to be capable of inducing ROS formation (62).”
Background
Elevated H2AX Phosphorylation Observed with kINPen Plasma Treatment Is Not Caused by ROS-Mediated DNA Damage but Is the Consequence of Apoptosis
Bekeschus, S., Schütz, C. S., Nießner, F., Wende, K., Weltmann, K., Gelbrich, N., von Woedtke, T., Schmidt, A., & Stope, M. B. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/8535163 · Cited by 58 · see citing works
Aeroallergens Induce Reactive Oxygen Species Production and DNA Damage and Dampen Antioxidant Responses in Bronchial Epithelial Cells
Chan, T. K., Tan, W. S. D., Peh, H. Y., & Wong, W. S. F. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1600657 · Cited by 55 · see citing works
“In addition, ROS is an important regulator of apoptotic cell death, which could be induced by excessive DNA damage (58, 59).”
Background
Long-term Persistent Organic Pollutants Exposure Induced Telomere Dysfunction and Senescence-Associated Secretary Phenotype
Yuan, J., Liu, Y., Wang, J., Zhao, Y., Li, K., Jing, Y., Zhang, X., Liu, Q., Geng, X., Li, G., et al. (2018) · The Journals of Gerontology: Series A · doi:10.1093/gerona/gly002 · Cited by 53 · see citing works
“And as we know, when exposed to environmental pollution, toxin damage, radiation exposure, or mental stress, the body will active the stress response process that could produce intracellular protein and DNA through cascade amplification and lead to aging inflammatory response (50,51) known as SASP.”
Background
Sinularin induces DNA damage, G2/M phase arrest, and apoptosis in human hepatocellular carcinoma cells
Chung, T.-W., Lin, S., Su, J., Chen, Y., Lin, C., & Chan, H. (2017) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-017-1583-9 · Cited by 58 · see citing works
“Given DNA damage usually comes along with oxidative stress and that reactive oxygen species (ROS) could be involved in leading to the mitochondria outer membrane permeabilization (MOMP) [23, 24], it is possible that sinularin induced oxidative DNA damage as well.”
Background
Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma
Chuang, J.-Y., Lo, W., Ko, C., Chou, S., Chen, R.-M., Chang, K.-Y., Hung, J., Su, W., Chang, W.-C., & Hsu, T.-I. (2017) · Oncogenesis · doi:10.1038/oncsis.2017.31 · Cited by 52
Single‐Atom Catalysts with Ultrahigh Catalase‐Like Activity Through Electron Filling and Orbital Energy Regulation
Wang, Z., Wang, W., Wang, J., Wang, D.-S., Liu, M., Wu, Q., & Hu, H.-Y. (2022) · Advanced Functional Materials · doi:10.1002/adfm.202209560 · Cited by 51 · see citing works
Glutathione boosting the cytotoxicity of a magnetic platinum( iv ) nano-prodrug in tumor cells
Zhu, Z., Wang, Z., Hao, Y., Zhu, C., Jiao, Y., Chen, H., Wang, Y., Yan, J., Guo, Z., & Wang, X. (2016) · Chemical Science · doi:10.1039/c5sc04049c · Cited by 69 · see citing works
Ionizing Radiation-Induced Brain Cell Aging and the Potential Underlying Molecular Mechanisms
Wang, Q., Yin, G., Huang, J., Xi, S.-J., Qian, F., Lee, R.-X., Peng, X., & Tang, F. R. (2021) · Cells · doi:10.3390/cells10123570 · Cited by 58 · see citing works
Dual Effects of Resveratrol on Cell Death and Proliferation of Colon Cancer Cells
Hipólito-Luengo, Á. S., Alcaide, A., Ramos-González, M., Cercas, E., Vallejo, S., Romero, A., Talero, E., Sánchez-Ferrer, C., Motilva, V., & Peiró, C. (2017) · Nutrition and Cancer · doi:10.1080/01635581.2017.1359309 · Cited by 50 · see citing works
“However, the over-activation of gH2AX may further increase the production of reactive oxygen species (26), which would then result in a potential mechanism to amplify and perpetuate the cytotoxic response of resveratrol.”
Background
Oxidative stress in abalone: The role of temperature, oxygen and l-proline supplementation
Vosloo, D., van Rensburg, L. V., & Vosloo, A. (2013) · Aquaculture · doi:10.1016/j.aquaculture.2013.09.031 · Cited by 50 · see citing works
Noncoding RNAs in DNA Repair and Genome Integrity
Wan, G., Liu, Y., Han, C., Zhang, X., & Lu, X. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5514 · Cited by 50 · see citing works
Brown algae phlorotannins enhance the tumoricidal effect of cisplatin and ameliorate cisplatin nephrotoxicity.
Yang, Y.-I., Ahn, J.-H., Choi, Y., & Choi, J.-H. (2015) · Gynecologic Oncology · doi:10.1016/j.ygyno.2014.11.015 · Cited by 49
Inhibition of p38 MAPK Signaling Augments Skin Tumorigenesis via NOX2 Driven ROS Generation
Liu, L., Rezvani, H. R., Back, J. H., Hosseini, M., Tang, X., Zhu, Y., Mahfouf, W., Raad, H., Raji, G. R., Athar, M., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097245 · Cited by 44 · see citing works
“group of enzymes, known as the NADPH oxidases, in which NOX is the catalytic subunit [4,5].”
Background
Chemically different non-thermal plasmas target distinct cell death pathways
Lunov, O., Zablotskii, V., Churpita, O., Lunová, M., Jirsa, M., Dejneka, A., & Kubinová, Š. (2017) · Scientific Reports · doi:10.1038/s41598-017-00689-5 · Cited by 53 · see citing works
Combination of a hypomethylating agent and inhibitors of PARP and HDAC traps PARP1 and DNMT1 to chromatin, acetylates DNA repair proteins, down-regulates NuRD and induces apoptosis in human leukemia and lymphoma cells
Valdez, B., Li, Y., Murray, D., Liu, Y., Nieto, Y., Champlin, R., & Andersson, B. (2017) · OncoTarget · doi:10.18632/oncotarget.23386 · Cited by 47 · see citing works
“Our results show increased ROS production and decreased mitochondrial membrane potential in both leukemia and lymphoma cell lines exposed to these drug combinations with a pattern that broadly parallels their effect on cytotoxicity (Figure 5).”
BackgroundInfluential
The Combination of MK-2206 and WZB117 Exerts a Synergistic Cytotoxic Effect Against Breast Cancer Cells
Li, Y.-L., Weng, H.-C., Hsu, J.-L., Lin, S.-W., Guh, J., & Hsu, L.-C. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01311 · Cited by 46
“On the other hand, DNA damage may also induce ROS through activation of H2AX (Kang et al., 2012).”
Background
Antibiotics-free nanomaterials against bacterial keratitis: Eliminating infections with reactive oxygen species (ROS)
Zhou, L., Deng, Y., Ren, Y.-J., Poon, H.-L., Chu, W.-Y., Wang, H., & Chan, Y.-K. (2024) · Chemical Engineering Journal · doi:10.1016/j.cej.2024.148978 · Cited by 44 · see citing works
Protective effect of curcumin against irinotecan‑induced intestinal mucosal injury via attenuation of NF‑κB activation, oxidative stress and endoplasmic reticulum stress.
Ouyang, M., Luo, Z.-T., Zhang, W., Zhu, D.-J., Lu, Y., Wu, J., & Yao, X.-Q. (2019) · International Journal of Oncology · doi:10.3892/ijo.2019.4714 · Cited by 44 · see citing works
Reactive oxygen species in cancer: a paradox between pro- and anti-tumour activities
Kohan, R., Collin, A., Guizzardi, S., de Talamoni, N. G. T., & Picotto, G. (2020) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-020-04103-2 · Cited by 41 · see citing works
Temporally distinct roles of ATM and ROS in genotoxic-stress-dependent induction and maintenance of cellular senescence
Nair, R. R., Bagheri, M., & Saini, D. K. (2014) · Journal of Cell Science · doi:10.1242/jcs.159517 · Cited by 38 · see citing works
“1B), similar to what has been reported previously (Kang et al., 2012).”
Result
ATM-NFκB axis-driven TIGAR regulates sensitivity of glioma cells to radiomimetics in the presence of TNFα
Sinha, S., Ghildiyal, R., Mehta, V., & Sen, E. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.128 · Cited by 41 · see citing works
“NCS induces cell death by triggering reactive oxygen species (ROS).(9) We have previously shown that ROS sensitizes glioma cells to chemotherapeutics.”
Background
Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents
Vekić, J., Zeljković, A., Stefanović, A., Giglio, R. V., Ciaccio, M., & Rizzo, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212409 · Cited by 46 · see citing works
DNA damage accumulation, defective chromatin organization and deficient DNA repair capacity in patients with rheumatoid arthritis
Souliotis, V. L., Vlachogiannis, N. I., Pappa, M. B., Argyriou, A., & Sfikakis, P. P. (2019) · Clinical Immunology · doi:10.1016/j.clim.2019.03.009 · Cited by 41 · see citing works
Reactive oxygen species in colorectal cancer: The therapeutic impact and its potential roles in tumor progression via perturbation of cellular and physiological dysregulated pathways
Moradi‐Marjaneh, R., Hassanian, S. M., Mehramiz, M., Rezayi, M., Ferns, G. A., Khazaei, M., & Avan, A. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27881 · Cited by 47 · see citing works
Redox-Mediated and Ionizing-Radiation-Induced Inflammatory Mediators in Prostate Cancer Development and Treatment
Miao, L., Holley, A. K., Zhao, Y., Clair, W. H. S., & Clair, D. K. S. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5637 · Cited by 41 · see citing works
“Two cell-surface G protein-coupled receptors, CXCR1 and CXCR2 (72), are responsible for the binding of IL-8 and regulating target gene expression through downstream signaling pathways, such as activation of serine/ threonine kinases, protein tyrosine kinases, and Rho-GTPases (189).”
H2A.X Phosphorylation in Oxidative Stress and Risk Assessment in Plasma Medicine
Schütz, C. S., Stope, M. B., & Bekeschus, S. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/2060986 · Cited by 41 · see citing works
“X is said to connect the DDR and ROS signaling pathways [85].”
Background
Catalase addition to vitrification solutions maintains goat ovarian preantral follicles stability.
Carvalho, A. A., Faustino, L. R., Silva, C. M., Castro, S. V., Lobo, C. H., Santos, F., Santos, R. R., Campello, C., Bordignon, V., Figueiredo, J., et al. (2014) · Research in Veterinary Science · doi:10.1016/j.rvsc.2014.05.006 · Cited by 38
“Cell cycle checkpoints and DNA repair are the most important cellular defenses against stress factors (Kang et al., 2012), and the histone H2AX phosphorylation is one of the major signs observed after DNA damage.”
Background
Gamma irradiation promotes chemo-sensitization potential of gallic acid through attenuation of autophagic flux to trigger apoptosis in NRF2 inactivation signalling pathway.
Patra, S., Bhol, C. S., Panigrahi, D. P., Praharaj, P., Pradhan, B., Jena, M., & Bhutia, S. (2020) · Free Radical Biology & Medicine · doi:10.1016/j.freeradbiomed.2020.06.022 · Cited by 37
Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance
Zhou, W., Sun, W., Yung, M. M. H., Dai, S., Cai, Y., Chen, C., Meng, Y., Lee, J. B., Braisted, J. C., Xu, Y., et al. (2018) · Oncogene · doi:10.1038/s41388-018-0238-8 · Cited by 41 · see citing works
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Background
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Authors: Kang, M. A., So, E.-Y., Simons, A. L., Spitz, D. R., & Ouchi, T.
Affiliations: Northwestern University (US)
National University of Health Sciences (US)
University of Iowa (US)
Corresponding author: Ouchi, T
ORCID: Kang, M A
Spitz, D R
Ouchi, T
Venue: Cell Death & Disease
Publisher: Springer Science and Business Media LLC
Published: 2012-01-12
Volume: 3
Issue: 1
Pages: e249-e249
ISSN: 2041-4889 (ISSN-L)
DOI: 10.1038/cddis.2011.134
PMC: PMC3270268
OpenAlex: W1983835791
Cited by: 311
References: 41
Citations by year: 2026: 11 · 2025: 35 · 2024: 20 · 2023: 25 · 2022: 14 · 2021: 26 · 2020: 25 · 2019: 26 · 2018: 22 · 2017: 30 · 2016: 12 · 2015: 16 · 2014: 27 · 2013: 15 · 2012: 7
FWCI: 8.36
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.springer.com/tdm (unspecified)
Locations: Cell Death and Disease (publishedVersion, cc-by-nc-nd)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Funders: Susan G. Komen
National Institutes of Health (R01CA90631)
National Cancer Institute (R01 CA90631, R01CA079892, R01CA090631, R01-CA79892, R01CA133114, T32CA078586, K01CA134941)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords: DNA damage response, reactive oxygen species, histone H2AX, NOX1, Rac1, NADPH oxidase, NOXA1, 14-3-3ζ, neocarzinostatin, ionizing radiation, N-acetylcysteine, DPI, cell death, antioxidants
MeSH terms: NADPH Oxidase 1, Acetylcysteine, Antioxidants, Cytotoxins, DNA Damage, Flow Cytometry, Histones, Humans, Zinostatin, Phosphorylation, Plasmids, Transfection, Signal Transduction, Gene Expression, Cell Death, Reactive Oxygen Species, NADPH Oxidases, rac1 GTP-Binding Protein, Adaptor Proteins, Vesicular Transport, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, 14-3-3 Proteins

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DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway

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