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oncology has gained significant attention, with its potential as a biomarker for cancer diagnosis and monitoring. However, its precise role in cancer biology and progression remains unclear. cfDNA in cancer patients\u2019 blood has been shown to activate signaling pathways, such as those mediated by toll-like receptors (TLRs), suggesting its involvement in cancer cell adaptation to the tumor microenvironment. Methods: This impact of cfDNA released from MDA-MB-231, a triple-negative breast cancer (TNBC) cell line was assessed, focusing on glucose availability and culture duration. The impact of cfDNA on the proliferation of MDA-MB-231 cells was investigated using proliferation curves, while cellular migration was evaluated through wound healing assays. The metabolic alterations induced by distinct cfDNA variants in MDA-MB-231 cells were investigated through nuclear magnetic resonance (NMR) spectroscopy, and their effect on cisplatin resistance was evaluated using flow cytometry. Furthermore, the expression levels of DNA-sensitive Toll-like receptor 9 (TLR9) were quantified via immunofluorescence, alongside its colocalization with lysosome-associated membrane protein 1 (LAMP1). Results: This study indicates that cfDNA facilitates metabolic adaptation, particularly under metabolic stress, by modulating glucose and glutamine consumption, key pathways in tumor cell metabolism. Exposure to cfDNA induced distinct metabolic shifts, favoring energy production through oxidative phosphorylation. The anti-cancer activity of cfDNA isolated from conditioned media of cells cultured under stressful conditions is influenced by the culture duration, emphasizing the importance of adaptation and se-lection in releasing cfDNA that can drive pro-tumoral processes. Additionally, cfDNA exposure influenced cell proliferation, quiescence, and migration, processes linked to metastasis and treatment resistance. These findings underscore cfDNA as a key mediator of metabolic reprogramming and adaptive responses in cancer cells, contributing to tumor progression and therapy resistance. Furthermore, the activation of TLR9 signaling suggests a mechanistic basis for cfDNA-induced phenotypic changes. Conclusions: Overall, cfDNA serves as a crucial signaling molecule in the tumor microenvironment, orchestrating adaptive processes that enhance cancer cell survival and progression.<\/jats:p>","DOI":"10.3390\/metabo15040227","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T03:35:28Z","timestamp":1743132928000},"page":"227","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cell-Free DNA (cfDNA) Regulates Metabolic Remodeling, Sustaining Proliferation, Quiescence, and Migration in MDA-MB-231, a Triple-Negative Breast Carcinoma (TNBC) Cell Line"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0568-905X","authenticated-orcid":false,"given":"Isabel","family":"Lemos","sequence":"first","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisbon, Portugal"},{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7570-0066","authenticated-orcid":false,"given":"Catarina","family":"Freitas-Dias","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisbon, Portugal"},{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal"}]},{"given":"Ana","family":"Hip\u00f3lito","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisbon, Portugal"},{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1927-164X","authenticated-orcid":false,"given":"Jos\u00e9","family":"Ramalho","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8985-1132","authenticated-orcid":false,"given":"Fabrizio","family":"Carteni","sequence":"additional","affiliation":[{"name":"Lab Applied Ecology and System Dynamics, Dipartimento di Agraria, Universit\u00e0 di Napoli \u201cFederico II\u201d, Portici, 80055 Naples, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5683-3552","authenticated-orcid":false,"given":"Lu\u00eds G.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier (ITQB NOVA), Avenida da Rep\u00fablica (EAN), 2780-157 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1132-2625","authenticated-orcid":false,"given":"Stefano","family":"Mazzoleni","sequence":"additional","affiliation":[{"name":"Lab Applied Ecology and System Dynamics, Dipartimento di Agraria, Universit\u00e0 di Napoli \u201cFederico II\u201d, Portici, 80055 Naples, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1548-5907","authenticated-orcid":false,"given":"Jacinta","family":"Serpa","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisbon, Portugal"},{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1111\/brv.12413","article-title":"The diverse origins of circulating cell-free DNA in the human body: A critical re-evaluation of the literature","volume":"93","author":"Aucamp","year":"2018","journal-title":"Biol. Rev. Camb. Philos. Soc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.bbcan.2016.03.006","article-title":"Use of cell free DNA in breast oncology","volume":"1865","author":"Canzoniero","year":"2016","journal-title":"Biochim. Et Biophys. Acta (BBA)-Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Duvvuri, B., and Lood, C. (2019). Cell-Free DNA as a Biomarker in Autoimmune Rheumatic Diseases. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00502"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Trulson, I., Stahl, J., Margraf, S., Scholz, M., Hoecherl, E., Wolf, K., Durner, J., Klawonn, F., and Holdenrieder, S. (2023). Cell-free DNA in plasma and serum indicates disease severity and prognosis in blunt trauma patients. Diagnostics, 13.","DOI":"10.3390\/diagnostics13061150"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Urosevic, N., Merritt, A.J., and Inglis, T.J. (2022). Plasma cfDNA predictors of established bacteraemic infection. Access Microbiol., 4.","DOI":"10.1099\/acmi.0.000373"},{"key":"ref_6","first-page":"646","article-title":"Free DNA in the serum of cancer patients and the effect of therapy","volume":"37","author":"Leon","year":"1977","journal-title":"Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s00421-010-1532-5","article-title":"Cell-free plasma DNA and purine nucleotide degradation markers following weightlifting exercise","volume":"110","author":"Atamaniuk","year":"2010","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1196\/annals.1448.002","article-title":"Overview of circulating nucleic acids in plasma\/serum: Update on potential prognostic and diagnostic value in diseases excluding fetal medicine and oncology","volume":"1137","author":"Butt","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1158\/1541-7786.MCR-16-0044","article-title":"Cell-free DNA (cfDNA): Clinical Significance and Utility in Cancer Shaped By Emerging Technologies","volume":"14","author":"Volik","year":"2016","journal-title":"Mol. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s13402-018-0413-5","article-title":"Cell-free DNA in cancer: Current insights","volume":"42","author":"Fettke","year":"2019","journal-title":"Cell Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.critrevonc.2017.12.002","article-title":"Circulating tumour DNA, a promising biomarker for the management of colorectal cancer","volume":"122","author":"Khakoo","year":"2018","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1002\/path.5395","article-title":"The stressful tumour environment drives plasticity of cell migration programmes, contributing to metastasis","volume":"250","author":"Nikolaou","year":"2020","journal-title":"J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.cmet.2018.11.018","article-title":"Starvation and pseudo-starvation as drivers of cancer metastasis through translation reprogramming","volume":"29","author":"Goding","year":"2019","journal-title":"Cell Metab."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Deng, S., Leong, H.C., Datta, A., Gopal, V., Kumar, A.P., and Yap, C.T. (2022). PI3K\/AKT signaling tips the balance of cytoskeletal forces for cancer progression. Cancers, 14.","DOI":"10.3390\/cancers14071652"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yan, Y.-y., Guo, Q.-r., Wang, F.-h., Adhikari, R., Zhu, Z.-y., Zhang, H.-y., Zhou, W.-m., Yu, H., Li, J.-q., and Zhang, J.-y. (2021). Cell-Free DNA: Hope and Potential Application in Cancer. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.639233"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.cell.2018.11.046","article-title":"Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding","volume":"176","author":"Gkountela","year":"2019","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s12943-019-0989-z","article-title":"The interplay of circulating tumor DNA and chromatin modification, therapeutic resistance, and metastasis","volume":"18","author":"Zhang","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_18","unstructured":"Mayrovitz, H.N. (2022). Subtypes of Breast Cancer, in Breast Cancer, Exon Publications."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Shaath, H., Elango, R., and Alajez, N.M. (2021). Molecular classification of breast cancer utilizing long non-coding RNA (lncRNA) transcriptomes identifies novel diagnostic lncRNA panel for triple-negative breast cancer. Cancers, 13.","DOI":"10.3390\/cancers13215350"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/35021093","article-title":"Molecular portraits of human breast tumours","volume":"406","author":"Perou","year":"2000","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"545","DOI":"10.31557\/APJCP.2022.23.2.545","article-title":"Circulating cell free DNA and DNA integrity index as discriminating tools between breast cancer and benign breast disease","volume":"23","author":"Elhelaly","year":"2022","journal-title":"Asian Pac. J. Cancer Prev. APJCP"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e12890","DOI":"10.1111\/acel.12890","article-title":"Cell-free DNA as a biomarker of aging","volume":"18","author":"Teo","year":"2019","journal-title":"Aging Cell"},{"key":"ref_23","first-page":"e42247","article-title":"Correlation between circulating cell-free DNA levels and breast cancer subtypes: A prospective observational study","volume":"15","author":"Pushpanjali","year":"2023","journal-title":"Cureus"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ferrari, P., Scatena, C., Ghilli, M., Bargagna, I., Lorenzini, G., and Nicolini, A. (2022). Molecular mechanisms, biomarkers and emerging therapies for chemotherapy resistant TNBC. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031665"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1097\/PPO.0000000000000501","article-title":"Tumor-infiltrating lymphocyctes in triple-negative breast cancer: Update for 2020","volume":"27","author":"Brown","year":"2021","journal-title":"Cancer J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.3892\/ijo.2020.5135","article-title":"Triple-negative breast cancer therapy: Current and future perspectives","volume":"57","author":"Won","year":"2020","journal-title":"Int. J. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"164","DOI":"10.5306\/wjco.v12.i3.164","article-title":"Overview of recent advances in metastatic triple negative breast cancer","volume":"12","author":"Kelly","year":"2021","journal-title":"World J. Clin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Nunes, S.C., Ramos, C., Lopes-Coelho, F., Sequeira, C.O., Silva, F., Gouveia-Fernandes, S., Rodrigues, A., Guimar\u00e3es, A., Silveira, M., and Abreu, S. (2018). Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-27753-y"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nunes, S.C., Ramos, C., Santos, I., Mendes, C., Silva, F., Vicente, J.B., Pereira, S.A., F\u00e9lix, A., Gon\u00e7alves, L.G., and Serpa, J. (2021). Cysteine Boosts Fitness Under Hypoxia-Mimicked Conditions in Ovarian Cancer by Metabolic Reprogramming. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.722412"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Nunes, S.C., Lopes-Coelho, F., Gouveia-Fernandes, S., Ramos, C., Pereira, S.A., and Serpa, J. (2018). Cysteine boosters the evolutionary adaptation to CoCl(2) mimicked hypoxia conditions, favouring carboplatin resistance in ovarian cancer. BMC Evol. Biol., 18.","DOI":"10.1186\/s12862-018-1214-1"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1089\/ars.2011.4391","article-title":"The cystine\/glutamate antiporter system x(c)(-) in health and disease: From molecular mechanisms to novel therapeutic opportunities","volume":"18","author":"Lewerenz","year":"2013","journal-title":"Antioxid. Redox Signal"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"303","DOI":"10.2147\/JEP.S267383","article-title":"Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy","volume":"13","author":"Tchounwou","year":"2021","journal-title":"J. Exp. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj2220001","article-title":"Free-radical mechanisms in tissue injury","volume":"222","author":"Slater","year":"1984","journal-title":"Biochem. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S0021-5198(19)43504-X","article-title":"Stimulatory effect of cisplatin on production of lipid peroxidation in renal tissues","volume":"43","author":"Sugihara","year":"1987","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Park, J.S., Rustamov, N., and Roh, Y.S. (2023). The Roles of NFR2-Regulated Oxidative Stress and Mitochondrial Quality Control in Chronic Liver Diseases. Antioxidants, 12.","DOI":"10.3390\/antiox12111928"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zang, H., Mathew, R.O., and Cui, T. (2020). The Dark Side of Nrf2 in the Heart. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00722"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bronkhorst, A.J., Ungerer, V., and Holdenrieder, S. (2019). The emerging role of cell-free DNA as a molecular marker for cancer management. Biomol. Detect. Quantif., 17.","DOI":"10.1016\/j.bdq.2019.100087"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Muinelo-Romay, L., Casas-Arozamena, C., and Abal, M. (2018). Liquid Biopsy in Endometrial Cancer: New Opportunities for Personalized Oncology. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082311"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5832","DOI":"10.1158\/1078-0432.CCR-18-4049","article-title":"Analysis of Cell-Free DNA from 32,989 Advanced Cancers Reveals Novel Co-occurring Activating RET Alterations and Oncogenic Signaling Pathway Aberrations","volume":"25","author":"Rich","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_40","first-page":"9467029","article-title":"Oxidized Cell-Free DNA Is a Factor of Stress Signaling in Radiation-Induced Bystander Effects in Different Types of Human Cells","volume":"2019","author":"Konkova","year":"2019","journal-title":"Int. J. Genom."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.drudis.2016.12.003","article-title":"Targeting amino acid metabolism for cancer therapy","volume":"22","author":"Lukey","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/j.chembiol.2017.08.028","article-title":"Targeting metabolism for cancer therapy","volume":"24","author":"Luengo","year":"2017","journal-title":"Cell Chem. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1038\/s12276-020-00504-8","article-title":"Glutamine reliance in cell metabolism","volume":"52","author":"Yoo","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.15252\/embj.201696151","article-title":"Cancer cell metabolism: The essential role of the nonessential amino acid, glutamine","volume":"36","author":"Zhang","year":"2017","journal-title":"EMBO J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1097\/PPO.0000000000000104","article-title":"Alternative fuels for cancer cells","volume":"21","author":"Keenan","year":"2015","journal-title":"Cancer J."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Moffatt, B.A., and Ashihara, H. (2002). Purine and pyrimidine nucleotide synthesis and metabolism. Arab. Book\/Am. Soc. Plant Biol., 1.","DOI":"10.1199\/tab.0018"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6747","DOI":"10.1038\/s41388-020-01480-z","article-title":"Multifaceted role of branched-chain amino acid metabolism in cancer","volume":"39","author":"Peng","year":"2020","journal-title":"Oncogene"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/nchembio.1961","article-title":"Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis","volume":"12","author":"Green","year":"2016","journal-title":"Nat. Chem. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"23668","DOI":"10.1074\/jbc.M402042200","article-title":"Arginase plays a pivotal role in polyamine precursor metabolism in Leishmania: Characterization of gene deletion mutants","volume":"279","author":"Roberts","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/s41568-018-0050-3","article-title":"Polyamine metabolism and cancer: Treatments, challenges and opportunities","volume":"18","author":"Pegg","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.canlet.2021.06.020","article-title":"Metabolism and function of polyamines in cancer progression","volume":"519","author":"Sari","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1006\/bbrc.1998.8258","article-title":"Structural specificity of polyamines and polyamine analogues in the protection of DNA from strand breaks induced by reactive oxygen species","volume":"244","author":"Ha","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/978-3-030-74180-8_10","article-title":"Role of L-Arginine in Nitric Oxide Synthesis and Health in Humans","volume":"1332","author":"Wu","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Yamamoto, N., Oyaizu, T., Enomoto, M., Horie, M., Yuasa, M., Okawa, A., and Yagishita, K. (2020). VEGF and bFGF induction by nitric oxide is associated with hyperbaric oxygen-induced angiogenesis and muscle regeneration. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-59615-x"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"13147","DOI":"10.1073\/pnas.0502979102","article-title":"Nitric oxide regulates angiogenesis through a functional switch involving thrombospondin-1","volume":"102","author":"Ridnour","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1002\/cbf.3637","article-title":"Gluconeogenesis is reduced from alanine, lactate and pyruvate, but maintained from glycerol, in liver perfusion of rats with early and late sepsis","volume":"39","author":"Biazi","year":"2021","journal-title":"Cell Biochem. Funct."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Hole\u010dek, M. (2024). Origin and roles of Alanine and glutamine in Gluconeogenesis in the liver, kidneys, and small intestine under physiological and pathological conditions. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25137037"},{"key":"ref_58","unstructured":"Dang, C., Gilewski, T.A., Surbone, A., and Norton, L. (2003). Growth curve analysis. Holland-Frei Cancer Medicine, BC Decker. [6th ed.]."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Diana, A., Carlino, F., Franzese, E., Oikonomidou, O., Criscitiello, C., De Vita, F., Ciardiello, F., and Orditura, M. (2020). Early triple negative breast cancer: Conventional treatment and emerging therapeutic landscapes. Cancers, 12.","DOI":"10.3390\/cancers12040819"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"105401","DOI":"10.1016\/j.ejps.2020.105401","article-title":"Understanding breast cancer: From conventional therapies to repurposed drugs","volume":"151","author":"Costa","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/cbf.1149","article-title":"The role of glutathione in cancer","volume":"22","author":"Balendiran","year":"2004","journal-title":"Cell Biochem. Funct."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1083\/jcb.201804161","article-title":"Glutathione metabolism in cancer progression and treatment resistance","volume":"217","author":"Bansal","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4183","DOI":"10.1167\/iovs.04-0570","article-title":"Cysteine starvation activates the redox-dependent mitochondrial permeability transition in retinal pigment epithelial cells","volume":"45","author":"Armstrong","year":"2004","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Chiang, F.-F., Chao, T.-H., Huang, S.-C., Cheng, C.-H., Tseng, Y.-Y., and Huang, Y.-C. (2022). Cysteine regulates oxidative stress and glutathione-related antioxidative capacity before and after colorectal tumor resection. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179581"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3907147","DOI":"10.1155\/2016\/3907147","article-title":"The interplay of reactive oxygen species, hypoxia, inflammation, and sirtuins in cancer initiation and progression","volume":"2016","author":"Tafani","year":"2016","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/s41419-019-2155-3","article-title":"Hypoxia regulates the mitochondrial activity of hepatocellular carcinoma cells through HIF\/HEY1\/PINK1 pathway","volume":"10","author":"Law","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1089\/ars.2017.7342","article-title":"Transcriptional regulation by Nrf2","volume":"29","author":"Tonelli","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Kostyuk, S.V., Konkova, M.S., Ershova, E.S., Alekseeva, A.J., Smirnova, T.D., Stukalov, S.V., Kozhina, E.A., Shilova, N.V., Zolotukhina, T.V., and Markova, Z.G. (2013). An exposure to the oxidized DNA enhances both instability of genome and survival in cancer cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0077469"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"S85","DOI":"10.1517\/14712598.2012.688948","article-title":"Extracellular DNA oxidation stimulates activation of NRF2 and reduces the production of ROS in human mesenchymal stem cells","volume":"12","author":"Loseva","year":"2012","journal-title":"Expert. Opin. Biol. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1245749","DOI":"10.1155\/2019\/1245749","article-title":"Oxidized Cell-Free DNA Role in the Antioxidant Defense Mechanisms under Stress","volume":"2019","author":"Filev","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Combs, J.A., and DeNicola, G.M. (2019). The Non-Essential Amino Acid Cysteine Becomes Essential for Tumor Proliferation and Survival. Cancers, 11.","DOI":"10.3390\/cancers11050678"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Tabata, S., Endo, H., Makinoshima, H., Soga, T., and Inoue, M. (2024). The \u03b3-glutamyl cycle serves as an amino acids supply system in colorectal cancer organoids under chronic hypoxia. Biochem. Biophys. Res. Commun., 714.","DOI":"10.1016\/j.bbrc.2024.149977"},{"key":"ref_73","first-page":"292","article-title":"Extracellular DNA secreted in yeast cultures is metabolism-specific and inhibits cell proliferation","volume":"10","author":"Incerti","year":"2023","journal-title":"Microb. Cell"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Palomba, E., Chiusano, M.L., Monticolo, F., Langella, M.C., Sanchez, M., Tirelli, V., de Alteriis, E., Iannaccone, M., Termolino, P., and Capparelli, R. (2024). Extracellular Self-DNA Effects on Yeast Cell Cycle and Transcriptome during Batch Growth. Biomolecules, 14.","DOI":"10.3390\/biom14060663"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Lindell, E., Zhong, L., and Zhang, X. (2023). Quiescent Cancer Cells-A Potential Therapeutic Target to Overcome Tumor Resistance and Relapse. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043762"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/s41419-021-04116-6","article-title":"The metabolic flexibility of quiescent CSC: Implications for chemotherapy resistance","volume":"12","author":"Chen","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s10555-022-10073-z","article-title":"Dormant cancer cells: Programmed quiescence, senescence, or both?","volume":"42","author":"Truskowski","year":"2023","journal-title":"Cancer Metastasis Rev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.semcancer.2019.09.007","article-title":"Cancer stem cells and their unique role in metastatic spread","volume":"60","author":"Steinbichler","year":"2020","journal-title":"Semin. Cancer Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2198","DOI":"10.1038\/s41467-024-46524-0","article-title":"Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory","volume":"15","author":"Michelatti","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"De Donatis, A., Ranaldi, F., and Cirri, P. (2010). Reciprocal control of cell proliferation and migration. Cell Commun. Signal., 8.","DOI":"10.1186\/1478-811X-8-20"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"172421","DOI":"10.1098\/rsos.172421","article-title":"Collective cell migration without proliferation: Density determines cell velocity and wave velocity","volume":"5","author":"Tlili","year":"2018","journal-title":"R. Soc. Open Sci."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Zanca, A., Flegg, J.A., and Osborne, J.M. (2022). Push or pull? Cell proliferation and migration during wound healing. Front. Syst. Biol., 2.","DOI":"10.3389\/fsysb.2022.876075"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Alfahed, A. (2024). Cell Migration\u2013Proliferation Dichotomy in Cancer: Biological Fact or Experimental Artefact?. Biology, 13.","DOI":"10.3390\/biology13100753"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1080\/15384101.2018.1442622","article-title":"Revisiting the Crabtree\/Warburg effect in a dynamic perspective: A fitness advantage against sugar-induced cell death","volume":"17","author":"Parascandola","year":"2018","journal-title":"Cell Cycle"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1038\/ni.1669","article-title":"Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9","volume":"9","author":"Park","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.4049\/jimmunol.1502357","article-title":"Complex negative regulation of TLR9 by multiple proteolytic cleavage events","volume":"197","author":"Sinha","year":"2016","journal-title":"J. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/icb.2008.101","article-title":"TLR9 traffics through the Golgi complex to localize to endolysosomes and respond to CpG DNA","volume":"87","author":"Chockalingam","year":"2009","journal-title":"Immunol. Cell Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/s41467-017-00695-1","article-title":"BAD-LAMP controls TLR9 trafficking and signalling in human plasmacytoid dendritic cells","volume":"8","author":"Combes","year":"2017","journal-title":"Nat. Commun."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/4\/227\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:02:52Z","timestamp":1760029372000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/4\/227"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,27]]},"references-count":88,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["metabo15040227"],"URL":"https:\/\/doi.org\/10.3390\/metabo15040227","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,27]]}}}