{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T10:54:50Z","timestamp":1771844090266,"version":"3.50.1"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T00:00:00Z","timestamp":1737331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Federal Ministry of Education and Research (BMBF)","award":["01KD2444"],"award-info":[{"award-number":["01KD2444"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Oxidative stress is universal to all cell types, including cancer. It is elicited by a surplus of reactive oxygen species (ROS) or a reduced cellular ability to defend against those. At low levels (oxidative eustress), this induces altered cellular signaling, while at higher levels (oxidative distress), cellular toxicity and non-specific redox signaling become apparent. While oxidation-induced cell death is a hallmark of many cancer therapies, including ROS-producing radiotherapy, some chemotherapies and targeted therapies, photodynamic therapy, and recently emerging physical modalities such as medical gas plasma (a multi-ROS generating technology), less is known about the transcriptional profiles predisposing cancer cells to oxidative demise. In particular, which genes are associated with resistance or sensitivity to ROS overload and subsequent toxicity has not been systematically investigated. Moreover, it is unclear if there are differences between oxidant types, such as hydrogen peroxide and hypochlorous acid. To this end, we here employed 35 cell lines of various origins (e.g., adenocarcinoma, melanoma, leukemia, squamous cell carcinoma, and neuroblastoma). We first performed in-house transcriptomic analysis to assess baseline transcriptional profiles. Second, all cell lines were exposed to four different ROS concentrations of either hydrogen peroxide, hypochlorous, or gas plasma exposure. Third, correlation analysis was performed to identify genes associated with (i) oxidative stress sensitivity, (ii) oxidative stress resistance, and (iii) similarities and\/or differences between the different oxidative stress inducers. Intriguingly, distinct gene sets were found for all treatments, and there was a striking difference between hydrogen peroxide and hypochlorous acid, suggesting different modes of action of both oxidants.<\/jats:p>","DOI":"10.3390\/cancers17020319","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T09:11:13Z","timestamp":1737364273000},"page":"319","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Transcriptional Pathways Predisposing to Cancer Oxidative Stress Sensitivity and Resistance Are Shared Between Hydrogen Peroxide and Cold Gas Plasma but Not Hypochlorous Acid"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2335-1607","authenticated-orcid":false,"given":"Debora","family":"Singer","sequence":"first","affiliation":[{"name":"Department of Dermatology and Venerology, Rostock University Medical Center, Strempelstr. 13, 18057 Rostock, Germany"},{"name":"ZIK <i>plasmatis<\/i>, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8773-8862","authenticated-orcid":false,"given":"Sander","family":"Bekeschus","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venerology, Rostock University Medical Center, Strempelstr. 13, 18057 Rostock, Germany"},{"name":"ZIK <i>plasmatis<\/i>, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41580-024-00730-2","article-title":"Fundamentals of redox regulation in biology","volume":"25","author":"Sies","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/s41580-022-00456-z","article-title":"Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology","volume":"23","author":"Sies","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2606928","DOI":"10.1155\/2022\/2606928","article-title":"Reactive Oxygen Species Bridge the Gap between Chronic Inflammation and Tumor Development","volume":"2022","author":"Yu","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12964-015-0118-6","article-title":"Hydrogen peroxide\u2014Production, fate and role in redox signaling of tumor cells","volume":"13","author":"Lennicke","year":"2015","journal-title":"Cell Commun. Signal."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0891-5849(00)00204-5","article-title":"Biomarkers of myeloperoxidase-derived hypochlorous acid","volume":"29","author":"Winterbourn","year":"2000","journal-title":"Free Radic. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Snell, J.A., Jandova, J., and Wondrak, G.T. (2022). Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.887220"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/JLB.3MR0717-292R","article-title":"Roles of neutrophils in cancer growth and progression","volume":"103","author":"Galdiero","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41573-024-00979-4","article-title":"Targeting ROS in cancer: Rationale and strategies","volume":"23","author":"Glorieux","year":"2024","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.clon.2007.03.010","article-title":"Chemical radiosensitizers for use in radiotherapy","volume":"19","author":"Wardman","year":"2007","journal-title":"Clin. Oncol. (R Coll Radiol.)"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nrc1071","article-title":"Photodynamic therapy for cancer","volume":"3","author":"Dolmans","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bekeschus, S. (2023). Medical gas plasma technology: Roadmap on cancer treatment and immunotherapy. Redox Biol., 65.","DOI":"10.1016\/j.redox.2023.102798"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bekeschus, S., von Woedtke, T., Emmert, S., and Schmidt, A. (2021). Medical gas plasma-stimulated wound healing: Evidence and mechanisms. Redox Biol., 46.","DOI":"10.1016\/j.redox.2021.102116"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4839","DOI":"10.7150\/thno.56747","article-title":"The double-edged roles of ROS in cancer prevention and therapy","volume":"11","author":"Wang","year":"2021","journal-title":"Theranostics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1515\/hsz-2020-0266","article-title":"Thiol switches in membrane proteins\u2014Extracellular redox regulation in cell biology","volume":"402","author":"Lorenzen","year":"2021","journal-title":"Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Bekeschus, S., Liebelt, G., Menz, J., Singer, D., Wende, K., and Schmidt, A. (2022). Cell cycle-related genes associate with sensitivity to hydrogen peroxide-induced toxicity. Redox Biol., 50.","DOI":"10.1016\/j.redox.2022.102234"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.2147\/DMSO.S453458","article-title":"Assessment of Reference Genes Stability in Cortical Bone of Obese and Diabetic Mice","volume":"17","author":"Ai","year":"2024","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ni, M., Li, Z., Li, J., He, H., Wang, Y., Jiang, Y., Wang, X., Li, Z., Li, M., and Xu, H. (2022). Selection and validation of reference genes for the normalization of quantitative real-time PCR in different muscle tissues of rabbits. BMC Zool., 7.","DOI":"10.1186\/s40850-022-00159-0"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"215049","DOI":"10.1016\/j.ccr.2023.215049","article-title":"Recent advances on modulation of H2O2 in tumor microenvironment for enhanced cancer therapeutic efficacy","volume":"481","author":"Chu","year":"2023","journal-title":"Coord. Chem. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rizo-Tellez, S.A., Sekheri, M., and Filep, J.G. (2022). Myeloperoxidase: Regulation of Neutrophil Function and Target for Therapy. Antioxidants, 11.","DOI":"10.3390\/antiox11112302"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"233001","DOI":"10.1088\/1361-6463\/aab3ad","article-title":"The kINPen-a review on physics and chemistry of the atmospheric pressure plasma jet and its applications","volume":"51","author":"Reuter","year":"2018","journal-title":"J. Phys. D-Appl. Phys."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3892\/or.2021.8022","article-title":"Hypochlorous acid selectively promotes toxicity and the expression of danger signals in human abdominal cancer cells","volume":"45","author":"Freund","year":"2021","journal-title":"Oncol. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"542","DOI":"10.3109\/10715762.2014.892937","article-title":"Hydrogen peroxide: A central player in physical plasma-induced oxidative stress in human blood cells","volume":"48","author":"Bekeschus","year":"2014","journal-title":"Free. Radic. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2200708119","DOI":"10.1073\/pnas.2200708119","article-title":"Gas plasma-oxidized sodium chloride acts via hydrogen peroxide in a model of peritoneal carcinomatosis","volume":"119","author":"Miebach","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/s41392-020-00326-0","article-title":"NADPH homeostasis in cancer: Functions, mechanisms and therapeutic implications","volume":"5","author":"Ju","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1158\/0008-5472.CAN-17-3155","article-title":"ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis","volume":"78","author":"Lu","year":"2018","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Liao, R., Ren, G., Liu, H., Chen, X., Cao, Q., Wu, X., Li, J., and Dong, C. (2018). ME1 promotes basal-like breast cancer progression and associates with poor prognosis. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-35106-y"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Shao, C., Lu, W., Du, Y., Yan, W., Bao, Q., Tian, Y., Wang, G., Ye, H., and Hao, H. (2020). Cytosolic ME1 integrated with mitochondrial IDH2 supports tumor growth and metastasis. Redox Biol., 36.","DOI":"10.1016\/j.redox.2020.101685"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3234","DOI":"10.1016\/j.jmb.2018.06.015","article-title":"Biliverdin Reductase B Dynamics Are Coupled to Coenzyme Binding","volume":"430","author":"Paukovich","year":"2018","journal-title":"J. Mol. Biol."},{"key":"ref_29","first-page":"119","article-title":"The multiple roles of amphiregulin in human cancer","volume":"1816","author":"Busser","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1074\/jbc.M706287200","article-title":"Epidermal growth factor receptor pathway analysis identifies amphiregulin as a key factor for cisplatin resistance of human breast cancer cells","volume":"283","author":"Eckstein","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"jcs258932","DOI":"10.1242\/jcs.258932","article-title":"Physiological functions and roles in cancer of the proliferation marker Ki-67","volume":"135","author":"Fisher","year":"2022","journal-title":"J. Cell Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.2147\/OTT.S296373","article-title":"Integrated Profiling Identifies CCNA2 as a Potential Biomarker of Immunotherapy in Breast Cancer","volume":"14","author":"Wang","year":"2021","journal-title":"Onco Targets Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5910575","DOI":"10.1155\/2022\/5910575","article-title":"CCNA2 as an Immunological Biomarker Encompassing Tumor Microenvironment and Therapeutic Response in Multiple Cancer Types","volume":"2022","author":"Jiang","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1002\/ppap.201300172","article-title":"Redox-Based Assay for Assessment of Biological Impact of Plasma Treatment","volume":"11","author":"Wende","year":"2014","journal-title":"Plasma Process. Polym."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/cbin.10360","article-title":"K562 cells display different vulnerability to H(2)O(2) induced oxidative stress in differing cell cycle phases","volume":"39","author":"Akcakaya","year":"2015","journal-title":"Cell Biol. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.freeradbiomed.2009.05.026","article-title":"The cell cycle is a redox cycle: Linking phase-specific targets to cell fate","volume":"47","author":"Burhans","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.tcb.2012.08.002","article-title":"Redox control of cell proliferation","volume":"22","author":"Chiu","year":"2012","journal-title":"Trends Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.3181\/0903-RM-98","article-title":"Cell cycle arrest induced by hydrogen peroxide is associated with modulation of oxidative stress related genes in breast cancer cells","volume":"234","author":"Chua","year":"2009","journal-title":"Exp. Biol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1477-3163-5-14","article-title":"Reactive oxygen species: Role in the development of cancer and various chronic conditions","volume":"5","author":"Waris","year":"2006","journal-title":"J. Carcinog."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/s12276-020-0384-2","article-title":"ROS in cancer therapy: The bright side of the moon","volume":"52","author":"Perillo","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1908164","DOI":"10.1155\/2016\/1908164","article-title":"Molecular and Cellular Effects of Hydrogen Peroxide on Human Lung Cancer Cells: Potential Therapeutic Implications","volume":"2016","author":"Arroyo","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3945","DOI":"10.1111\/cas.15068","article-title":"Reactive oxygen species in cancer: Current findings and future directions","volume":"112","author":"Nakamura","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5191","DOI":"10.1158\/0008-5472.CAN-19-0515","article-title":"Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia","volume":"79","author":"Hosseini","year":"2019","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2003395","DOI":"10.1002\/advs.202003395","article-title":"Gas Plasma Technology Augments Ovalbumin Immunogenicity and OT-II T Cell Activation Conferring Tumor Protection in Mice","volume":"8","author":"Clemen","year":"2021","journal-title":"Adv. Sci."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/2\/319\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:31:59Z","timestamp":1759919519000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/2\/319"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,20]]},"references-count":44,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["cancers17020319"],"URL":"https:\/\/doi.org\/10.3390\/cancers17020319","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,20]]}}}