{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T12:53:02Z","timestamp":1780491182090,"version":"3.54.1"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T00:00:00Z","timestamp":1721260800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["20K11626"],"award-info":[{"award-number":["20K11626"]}]},{"name":"Fordays Co., Ltd"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The nucleic acids found in food play a crucial role in maintaining various bodily functions. This study investigated the potential anticancer effects of dietary nucleic acids, an area that is still not fully understood. By utilizing an <jats:italic>in vivo<\/jats:italic> mouse model and an <jats:italic>in vitro<\/jats:italic> cell model, we discovered an anti-proliferative impact of RNA in both systems. DNA exhibited anti-proliferative effects in the mouse model, while this phenomenon wasn\u2019t observed in the <jats:italic>in vitro<\/jats:italic> cell model using Ehrlich ascites tumor (EAT) cells. Conversely, DNA hydrolysate demonstrated distinct anti-proliferative effects in EAT cells, suggesting that nucleotides or nucleosides generated during nucleic acid digestion act as active constituents. Furthermore, we examined various nucleosides and two sodium-independent equilibrative nucleoside transporter inhibitors (ENTs), identifying guanosine and 2\u2019-deoxyguanosine as pivotal in the anti-proliferative effect. We also found that the anti-proliferation activity with both nucleosides was suppressed by the treatment of dipyridamole, a non-selective inhibitor for ENT1 and ENT2, but not nitrobenzylthioinosine, a low inhibitor for ENT2. The uptake of these compounds into cells is likely facilitated by ENT2. These nucleotides impeded the progression of cancer cells from the G1 phase to the S phase in the cell cycle. Another significant finding is the increased expression of CCAAT\/enhancer-binding protein (C\/EBP\u03b2) induced by guanosine and 2\u2019-deoxyguanosine. Furthermore, immunostaining revealed that C\/EBP\u03b2 diffuses into the nucleus, indicating its presence. This suggests that guanosine or 2-deoxyguanosine induces G1 arrest in cancer cells via the activation of C\/EBP\u03b2. Encouraged by these promising results, guanosine and 2\u2019-deoxyguanosine show potential applications in cancer prevention.<\/jats:p>","DOI":"10.1371\/journal.pone.0305775","type":"journal-article","created":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T17:47:21Z","timestamp":1721324841000},"page":"e0305775","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Suppression of Ehrlich ascites tumor cell proliferation via G1 arrest induced by dietary nucleic acid-derived nucleosides"],"prefix":"10.1371","volume":"19","author":[{"given":"Nahoko","family":"Shiomi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamia","family":"Furuta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaro","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isao","family":"Matsui-Yuasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Kiriyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mica","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0028-1709","authenticated-orcid":true,"given":"Keita","family":"Sutoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8167-3693","authenticated-orcid":true,"given":"Akiko","family":"Kojima-Yuasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,7,18]]},"reference":[{"key":"pone.0305775.ref001","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1651-2227.1999.tb01306.x","article-title":"Dietary nucleotides: Effects on the immune and gastrointestinal systems","volume":"88","author":"JD Carver","year":"1999","journal-title":"Acta Paediatr"},{"key":"pone.0305775.ref002","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/S0899-9007(00)00287-2","article-title":"Dietary nucleotides modulate antigen-specific type 1 and type 2 T-cell responses in young c57bl\/6 mice","volume":"16","author":"H Jyonouchi","year":"2000","journal-title":"Nutrition"},{"key":"pone.0305775.ref003","first-page":"132","article-title":"Dietary nucleic acid and intestinal microbiota synergistically promote a shift in the Th1\/Th2 balance toward Th1-dominant immunity","volume":"135","author":"N Sudo","year":"2004","journal-title":"Clin. Exp. Allergy"},{"key":"pone.0305775.ref004","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/978-1-4615-5381-6_105","article-title":"Changes of polymorphonuclear leukocyte (PMN) functions under dietary nucleic acid deficiency and effects of administration of nucleotides mixture solution in mice","volume":"431","author":"A Hirai","year":"1998","journal-title":"Adv. Exp. Med. Biol"},{"key":"pone.0305775.ref005","doi-asserted-by":"crossref","first-page":"73","DOI":"10.3177\/jnsv.61.73","article-title":"Dietary ribonucleic acid suppresses inflammation of adipose tissue and improves glucose intolerance that is Mediated by immune cells in C57BL\/6 mice fed a high-fat diet","volume":"61","author":"T Sakai","year":"2015","journal-title":"J. Nutr. Sci. Vitamminol"},{"key":"pone.0305775.ref006","article-title":"Protective effects of hydrolyzed nucleoproteins from salmon mill against ethanol-induced liver injury in rats","volume":"232","author":"A Kojima-Yuasa","year":"2016","journal-title":"Mar. Drugs"},{"key":"pone.0305775.ref007","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.neuint.2012.05.021","article-title":"Guanosine protects human neuroblastoma SH-SY5Y cells against mitochondrial oxidative stress by inducing heme oxygenase-1 via PI3K\/Akt\/GSK-3 \u03b2 pathway","volume":"61","author":"T Dal-Cim","year":"2012","journal-title":"Neurochem, Inter"},{"key":"pone.0305775.ref008","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s12640-018-9976-1","article-title":"Guanosine protects striatal slices against 6-OHDA-induced oxidative damage, mitochondrial dysfunction, and ATP depletion","volume":"35","author":"NF Marques","year":"2019","journal-title":"Neurotoxicity Res"},{"key":"pone.0305775.ref009","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.3390\/jcm12031172","article-title":"Influence of Guanine-based purines on the oxidoreductive reactions involved in normal or altered brain functions","volume":"12","author":"M Zuccarini","year":"2023","journal-title":"J. Clin. Med"},{"key":"pone.0305775.ref010","doi-asserted-by":"crossref","first-page":"657","DOI":"10.14336\/AD.2016.0208","article-title":"Guanosine: a neuromodulator with therapeutic potential in brain disorders","volume":"7","author":"D Lanznaster","year":"2016","journal-title":"Aging Dis"},{"key":"pone.0305775.ref011","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1016\/j.bbamem.2010.09.020","article-title":"Adenosine receptors and cancer","volume":"1808","author":"S Gessi","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"pone.0305775.ref012","article-title":"Guanine inhibits the growth of human glioma and melanoma cell lines by interacting with GPR23. Front","author":"R Garozzo","year":"2022","journal-title":"Pharmacol"},{"key":"pone.0305775.ref013","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1007\/BF02977621","article-title":"Effects of guanosine on the pharmacokinetics of acriflavine and guanosine, potential antitumor agent","volume":"30","author":"PS Lee","year":"2007","journal-title":"Arch. Pharma. Res"},{"key":"pone.0305775.ref014","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/BF00296258","article-title":"Potentiation of the chemotherapeutic action of 5\u2019-deoxy 5-fluouridine in combination with guanosine and related compounds","volume":"19","author":"M Iigo","year":"1987","journal-title":"Cancer Chemother. Pharmacol"},{"key":"pone.0305775.ref015","doi-asserted-by":"crossref","first-page":"3301","DOI":"10.1038\/sj.emboj.7600789","article-title":"C\/EBP\u03b2 cooperates with RB; E2F to implement RasV12-induced cellular senescence","volume":"24","author":"T Sebastian","year":"2005","journal-title":"EMBO J"},{"key":"pone.0305775.ref016","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s12885-023-10543-9","article-title":"C\/EBP\u03b2 expression decreases in cervical cancer and leads to tumorigenesis","volume":"23","author":"H Long","year":"2023","journal-title":"BMC Cancer"},{"key":"pone.0305775.ref017","doi-asserted-by":"crossref","first-page":"5583","DOI":"10.3390\/molecules25235583","article-title":"Natural phenolic acid, product of the honey bee, for the control of oxidative stress, peritoneal angiogenesis, and tumor growth in mice","volume":"25","author":"N Or\u0161oli\u0107","year":"2020","journal-title":"Molecules"},{"key":"pone.0305775.ref018","doi-asserted-by":"crossref","first-page":"115851","DOI":"10.1016\/j.taap.2021.115851","article-title":"Resveratrol and its nanocrystals: A promising approach for cancer therapy?","volume":"435","author":"D An\u010di\u0107","year":"2022","journal-title":"Toxicol. Appli. Pharmacol"},{"key":"pone.0305775.ref019","first-page":"163","volume-title":"Methods in Enzymology","author":"Academic Press","year":"1968"},{"key":"pone.0305775.ref020","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.bcp.2013.08.063","article-title":"Dipyridamole analogs as pharmacological inhibitors of equilibrative nucleoside transporters; Identification of novel potent and selective equilibrative nucleoside transporter 4 (hENT4)","volume":"86","author":"C Wang","year":"2013","journal-title":"Biochem. pharmacol"},{"key":"pone.0305775.ref021","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0304-4157(96)00008-1","article-title":"Nucleoside and nucleobase transport systems of mammalian cells","volume":"1286","author":"DA Griffith","year":"1996","journal-title":"Biochim. Biophys. Acta"},{"key":"pone.0305775.ref022","doi-asserted-by":"crossref","first-page":"8375","DOI":"10.1074\/jbc.275.12.8375","article-title":"Kinetic and pharmacological properties of human equilibrative nucleoside transporters, ENT1 and ENT2 stably expressed in nucleoside transporter-dependent PK15 cells. ENT2 exhibits a low affinity for guanosine and cytidine, but a high affinity for inosine","volume":"275","author":"J Ward","year":"2000","journal-title":"J. Biol, Chem"},{"key":"pone.0305775.ref023","doi-asserted-by":"crossref","first-page":"953","DOI":"10.4161\/cc.5.9.2733","article-title":"Stop and go: anti-proliferative and mitogenic functions of the transcription factor C\/EBPbeta","volume":"5","author":"T Sebastian","year":"2006","journal-title":"Cell Cycle"},{"key":"pone.0305775.ref024","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.neuroscience.2010.12.025","article-title":"Decreased CCAAT\/enhancer binding protein beta expression inhibits the growth of glioblastoma cells","volume":"176","author":"D Aguilar-Morante","year":"2011","journal-title":"Neurosci"},{"key":"pone.0305775.ref025","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1002\/j.1460-2075.1994.tb06328.x","article-title":"LAP(NF-IL-6), a tissue-specific transcriptional activator, is an inhibitor of hepatoma cell proliferation","volume":"13","author":"M Buck","year":"1994","journal-title":"EMBO J"},{"key":"pone.0305775.ref026","first-page":"e14346","article-title":"Salmon sperm DNA prevents acute liver injury by regulating alcohol-induced steatosis and restores chronic hepatitis via alleviating inflammation and apoptosis","volume":"46","author":"Y Xue","year":"2022","journal-title":"J. Food Biochem"},{"key":"pone.0305775.ref027","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.3390\/ijms15022024","article-title":"Adenosine receptors; expression, function and regulation","volume":"15","author":"S Sheth","year":"2014","journal-title":"Int. J. Mol. Sci"},{"key":"pone.0305775.ref028","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1159\/000325207","article-title":"Adenosine activates AMPK to Phosphorylase Bcl-XI, responsible for mitochondrial damage and DIABLO release in HuH-7 cells","volume":"27","author":"D Yang","year":"2011","journal-title":"Cell. Physiol. Biochem"},{"key":"pone.0305775.ref029","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/biof.5520270119","article-title":"Mechanisms of adenosine-induced cytotoxicity and their clinical and physiological implications. Mechanisms of adenosine-induced cytotoxicity and their clinical and physiological implications","volume":"27","author":"SP Seetulsight-Goorah","year":"2006","journal-title":"BioFactors"},{"key":"pone.0305775.ref030","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1111\/j.2042-7158.1997.tb06783.x","article-title":"Enhanced anti-tumor effects of acriflavine in combination with guanosine in mice","volume":"49","author":"SG Kim","year":"1997","journal-title":"J. Pharm. Pharmacol"},{"key":"pone.0305775.ref031","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1007\/BF02977621","article-title":"Effects of guanosine on the pharmacokinetics of acriflavine and guanosine, a potential antitumor agent","volume":"30","author":"PS Lee","year":"2007","journal-title":"Arch. Pharm. Res"},{"key":"pone.0305775.ref032","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/BF00296258","article-title":"Potentiation of the chemotherapeutic action of 5\u2019-fluorouridine in combination with guanosine and related compounds","volume":"19","author":"M Iigo","year":"1987","journal-title":"Cancer Chemother. Pharmacol"},{"key":"pone.0305775.ref033","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s11302-017-9562-7","article-title":"Guanosine promotes cytotoxicity via adenosine receptors and induces apoptosis in temozolomide-treated A172 glioma cells","volume":"13","author":"KA Oliveira","year":"2017","journal-title":"Purinergic Signaling"},{"key":"pone.0305775.ref034","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/S0026-0495(97)90210-9","article-title":"Close correlation between visceral fat accumulation and uric acid metabolism in healthy men","volume":"46","author":"S Takahashi","year":"1997","journal-title":"Metabolism"},{"key":"pone.0305775.ref035","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1056\/NEJM198212233072602","article-title":"Ethanol-induced hyperuricemia: evidence for increased urate production by activation of adenine nucleotide turnover","volume":"307","author":"J Faller","year":"1982","journal-title":"N Engl J Med"},{"key":"pone.0305775.ref036","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0021-9258(18)56639-4","article-title":"The metabolism of uric acid in the normal and gouty human studied with the aid of isotopic uric acid","volume":"181","author":"JD Benedict","year":"1949","journal-title":"J Biol Chem"},{"key":"pone.0305775.ref037","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1172\/JCI104360","article-title":"Uric acid production in gout","volume":"40","author":"JE Seegmiller","year":"1961","journal-title":"J Clin Invest"},{"key":"pone.0305775.ref038","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3000237","article-title":"Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population","volume":"1","author":"H Matsuo","year":"2009","journal-title":"Sci Transl Med"},{"key":"pone.0305775.ref039","doi-asserted-by":"crossref","first-page":"k3951","DOI":"10.1136\/bmj.k3951","article-title":"Evaluation of the diet wide contribution to serum urate levels: meta-analysis of population based cohorts","volume":"363","author":"TJ Major","year":"2018","journal-title":"BMJ"},{"key":"pone.0305775.ref040","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.mam.2012.05.007","article-title":"The human concentrative and equilibrative nucleoside transporter families, SLC28, SLC29","volume":"34","author":"JD Young","year":"2012","journal-title":"Mol Aspects Med"},{"key":"pone.0305775.ref041","doi-asserted-by":"crossref","first-page":"15880","DOI":"10.1074\/jbc.M414337200","article-title":"Functional characterization of novel human and mouse equilibrative nucleoside transporters (hENT3 and mENT3) located in intracellular membrans","volume":"280","author":"SA Baldwin","year":"2005","journal-title":"J. Biol. Chem"},{"key":"pone.0305775.ref042","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1161\/01.RES.0000238359.18495.42","article-title":"Distribution and functional characterization of equilibrative nucleoside transporter-4, a novel cardiac adenosine transporter activated at acidic pH","volume":"99","author":"K Barnes","year":"2006","journal-title":"Circ. Res"},{"key":"pone.0305775.ref043","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.bbrc.2021.04.075","article-title":"Characterization of deoxyribonucleoside transport mediated by concentrative nucleoside transporters","volume":"558","author":"T Yamamura","year":"2021","journal-title":"Biochemical and Biophysical Research Communications"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0305775","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T17:47:55Z","timestamp":1721324875000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0305775"}},"subtitle":[],"editor":[{"given":"Yuqi","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,7,18]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7,18]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0305775","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,18]]}}}