{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T23:12:00Z","timestamp":1770333120578,"version":"3.49.0"},"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016263","name":"University Research Board, American University of Beirut","doi-asserted-by":"publisher","award":["103605"],"award-info":[{"award-number":["103605"]}],"id":[{"id":"10.13039\/501100016263","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Practice Plan"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Hypoxic stress in solid tumors triggers growth arrest and apoptosis through p53 activation and stabilization. This environment inactivates p53 and drives the expansion of p53-mutant clones, which accentuate tumor aggressiveness. Ceramide, a signaling sphingolipid, was previously identified as a downstream collaborator with p53 in the stress-induced apoptosis and cell cycle arrest. Among sphingolipids, the balance between pro- and anti-apoptotic products, dictated by the expression and activity of appropriate enzymes, helps determine cell fate in response to hypoxia. The current study aimed to understand the role of ceramide in HCT116 human colon cancer cells response to hypoxia in the presence or absence of p53, and to determine whether the modulation of ceramide metabolism could sensitize the resistant p53-deficient cells to hypoxia-induced cell death. We observed that HCT116 p53-deficient cells were resistant to hypoxic cell death. We explored the role of ceramide in this response by screening for different sphingolipid metabolites through liquid-chromatography-mass spectrometry, and by measuring the expression of key enzymes involved in ceramide biosynthesis and breakdown. We also evaluated the changes in the cellular response to hypoxia associated with introduction of sphingolipid metabolites or with modulating the activity of related sphingolipid-metabolizing enzymes. In hypoxic p53-deficient cells, ceramide was synthesized via the\n                    <jats:italic>de novo<\/jats:italic>\n                    pathway through the action of ceramide synthases and dihydroceramide desaturase (DEGS1) driving the evasion of hypoxia-induced apoptosis. Among the accumulating ceramide species in p53 deficient cells, C24-ceramide was the most abundant and possibly contributing to their resistance. Tipping the sphingolipid balance in favor of pro-apoptotic sphingolipids, through the addition of C6 ceramide or sphingosine, or through the combined pharmacologic inhibition of DEGS1 and sphingosine kinase 1, helped circumvent the cellular resistance to hypoxia-induced apoptosis in cells lacking p53. Therefore, modulating sphingolipid metabolism may be a viable approach in the treatment of solid tumors with hypoxic regions.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0340295","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T18:49:51Z","timestamp":1767725391000},"page":"e0340295","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting ceramide metabolism to restore hypoxia-induced apoptosis in p53-deficient colon cancer cells"],"prefix":"10.1371","volume":"21","author":[{"given":"Karen","family":"Mechleb","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0597-0044","authenticated-orcid":true,"given":"Nancy","family":"Hourani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1274-9348","authenticated-orcid":true,"given":"Maya","family":"Fakhry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osama A.","family":"Alyamani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rouba","family":"Hage-Sleiman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hicham","family":"Younes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoine Abou","family":"Fayad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia","family":"Soudani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amer","family":"Sakr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1862-5426","authenticated-orcid":true,"given":"Nadine","family":"Darwiche","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2157-5279","authenticated-orcid":true,"given":"Georges","family":"Nemer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5776-2303","authenticated-orcid":true,"given":"Raya","family":"Saab","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marguerite","family":"Mrad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghassan","family":"Dbaibo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"issue":"1","key":"pone.0340295.ref001","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/nrc704","article-title":"Hypoxia--a key regulatory factor in tumour growth","volume":"2","author":"AL Harris","year":"2002","journal-title":"Nat Rev Cancer"},{"issue":"14","key":"pone.0340295.ref002","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.3390\/cells14141057","article-title":"Influence of Hypoxia on Tumor Heterogeneity, DNA Repair, and Cancer Therapy: From Molecular Insights to Therapeutic Strategies","volume":"14","author":"D Kunachowicz","year":"2025","journal-title":"Cells"},{"issue":"1","key":"pone.0340295.ref003","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/35094077","article-title":"Rescuing the function of mutant p53","volume":"1","author":"AN Bullock","year":"2001","journal-title":"Nat Rev Cancer"},{"issue":"7128","key":"pone.0340295.ref004","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/nature05541","article-title":"Restoration of p53 function leads to tumour regression in vivo","volume":"445","author":"A Ventura","year":"2007","journal-title":"Nature"},{"issue":"1","key":"pone.0340295.ref005","doi-asserted-by":"crossref","first-page":"80","DOI":"10.2174\/1389450114666140106101412","article-title":"Targeting tumor suppressor p53 for cancer therapy: strategies, challenges and opportunities","volume":"15","author":"B Hong","year":"2014","journal-title":"Curr Drug Targets"},{"issue":"3","key":"pone.0340295.ref006","doi-asserted-by":"crossref","first-page":"4982","DOI":"10.3390\/ijms14034982","article-title":"p53 and Ceramide as Collaborators in the Stress Response","volume":"14","author":"R Hage-Sleiman","year":"2013","journal-title":"Int J Mol Sci"},{"issue":"17","key":"pone.0340295.ref007","doi-asserted-by":"crossref","first-page":"9697","DOI":"10.3390\/ijms23179697","article-title":"Ceramide Acyl Chain Length and Its Relevance to Intracellular Lipid Regulation","volume":"23","author":"QWC Ho","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"4","key":"pone.0340295.ref008","doi-asserted-by":"crossref","DOI":"10.1016\/j.biocel.2011.12.019","article-title":"Long chain ceramides and very long chain ceramides have opposite effects on human breast and colon cancer cell growth","volume":"44","author":"D Hartmann","year":"2012","journal-title":"Int J Biochem Cell Biol"},{"issue":"12","key":"pone.0340295.ref009","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0190221","article-title":"Genomic alterations during p53-dependent apoptosis induced by \u03b3-irradiation of Molt-4 leukemia cells","volume":"12","author":"R Hage-Sleiman","year":"2017","journal-title":"PLoS One"},{"key":"pone.0340295.ref010","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s11010-020-03874-9","article-title":"Crosstalk between Noxa, Bcl-2, and ceramide in mediating p53-dependent apoptosis in Molt-4 human T-cell leukemia","volume":"475","author":"H Kobeissy","year":"2020","journal-title":"Mol Cell Biochem"},{"key":"pone.0340295.ref011","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.prostaglandins.2008.02.004","article-title":"De novo N-palmitoylsphingosine synthesis is the major biochemical mechanism of ceramide accumulation following p53 up-regulation","volume":"86","author":"S Panjarian","year":"2008","journal-title":"Prostaglandins Other Lipid Mediat"},{"issue":"2","key":"pone.0340295.ref012","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1172\/JCI1180","article-title":"p53-dependent ceramide response to genotoxic stress","volume":"102","author":"GS Dbaibo","year":"1998","journal-title":"J Clin Invest"},{"issue":"6","key":"pone.0340295.ref013","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1089\/dna.2013.1993","article-title":"Regulation of de novo ceramide synthesis: the role of dihydroceramide desaturase and transcriptional factors NFATC and Hand2 in the hypoxic mouse heart","volume":"32","author":"R Azzam","year":"2013","journal-title":"DNA Cell Biol"},{"issue":"2","key":"pone.0340295.ref014","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1203\/00006450-200202000-00005","article-title":"Modulation of ceramide content and lack of apoptosis in the chronically hypoxic neonatal rat heart","volume":"51","author":"FF Bitar","year":"2002","journal-title":"Pediatr Res"},{"key":"pone.0340295.ref015","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.prostaglandins.2008.02.003","article-title":"Modulation of total ceramide and constituent ceramide species in the acutely and chronically hypoxic mouse heart at different ages","volume":"86","author":"L Noureddine","year":"2008","journal-title":"Prostaglandins Other Lipid Mediat"},{"issue":"44","key":"pone.0340295.ref016","doi-asserted-by":"crossref","first-page":"38069","DOI":"10.1074\/jbc.M111.297994","article-title":"Dihydroceramide-based response to hypoxia","volume":"286","author":"CM Devlin","year":"2011","journal-title":"Journal of Biological Chemistry"},{"issue":"4","key":"pone.0340295.ref017","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.cellsig.2009.11.015","article-title":"Hypoxia-induced neuronal apoptosis is mediated by de novo synthesis of ceramide through activation of serine palmitoyltransferase","volume":"22","author":"MS Kang","year":"2010","journal-title":"Cell Signal"},{"key":"pone.0340295.ref018","doi-asserted-by":"crossref","first-page":"178910","DOI":"10.1155\/2013\/178910","article-title":"Sphingolipid metabolic pathway: an overview of major roles played in human diseases","volume":"2013","author":"R Pralhada Rao","year":"2013","journal-title":"J Lipids"},{"issue":"3","key":"pone.0340295.ref019","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.3390\/ijms26031056","article-title":"Sphingosine-1-Phosphate Metabolic Pathway in Cancer: Implications for Therapeutic Targets","volume":"26","author":"ML Rufail","year":"2025","journal-title":"Int J Mol Sci"},{"key":"pone.0340295.ref020","article-title":"Short periods of hypoxia upregulate Sphingosine Kinase 1 and increase vasodilation of arteries to Sphingosine 1-Phosphate via S1P3","author":"H Alganga","year":"2019","journal-title":"J Pharmacol Exp Ther [Internet]"},{"issue":"6","key":"pone.0340295.ref021","doi-asserted-by":"crossref","first-page":"3365","DOI":"10.1074\/jbc.M708241200","article-title":"Sphingosine kinase 1 is up-regulated during hypoxia in U87MG glioma cells. Role of hypoxia-inducible factors 1 and 2","volume":"283","author":"V Anelli","year":"2008","journal-title":"J Biol Chem"},{"issue":"20","key":"pone.0340295.ref022","doi-asserted-by":"crossref","first-page":"8635","DOI":"10.1158\/0008-5472.CAN-08-0917","article-title":"Sphingosine kinase 1: a new modulator of hypoxia inducible factor 1alpha during hypoxia in human cancer cells","volume":"68","author":"I Ader","year":"2008","journal-title":"Cancer Res"},{"issue":"5393","key":"pone.0340295.ref023","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1126\/science.282.5393.1497","article-title":"Requirement for p53 and p21 to sustain G2 arrest after DNA damage","volume":"282","author":"F Bunz","year":"1998","journal-title":"Science"},{"key":"pone.0340295.ref024","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/978-1-60761-322-0_22","article-title":"Comprehensive quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry","volume":"579","author":"J Bielawski","year":"2009","journal-title":"Methods Mol Biol"},{"issue":"8","key":"pone.0340295.ref025","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1139\/o59-099","article-title":"A rapid method of total lipid extraction and purification","volume":"37","author":"EG Bligh","year":"1959","journal-title":"Can J Biochem Physiol"},{"key":"pone.0340295.ref026"},{"key":"pone.0340295.ref027"},{"issue":"28","key":"pone.0340295.ref028","doi-asserted-by":"crossref","first-page":"24754","DOI":"10.1074\/jbc.M111.250779","article-title":"Identification of dihydroceramide desaturase as a direct in vitro target for fenretinide","volume":"286","author":"M Rahmaniyan","year":"2011","journal-title":"J Biol Chem"},{"key":"pone.0340295.ref029","doi-asserted-by":"crossref","first-page":"331","DOI":"10.3389\/fphys.2014.00331","article-title":"Inhibition of acid sphingomyelinase by tricyclic antidepressants and analogons","volume":"5","author":"N Beckmann","year":"2014","journal-title":"Front Physiol"},{"key":"pone.0340295.ref030","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/S0014-5793(04)00033-X","article-title":"Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine","volume":"559","author":"M K\u00f6lzer","year":"2004","journal-title":"FEBS Lett"},{"key":"pone.0340295.ref031","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S1388-1981(02)00336-0","article-title":"Sphingosine in apoptosis signaling","volume":"1585","author":"O Cuvillier","year":"2002","journal-title":"Biochim Biophys Acta"},{"issue":"3","key":"pone.0340295.ref032","doi-asserted-by":"crossref","first-page":"284","DOI":"10.2174\/157489211796957838","article-title":"Ceramide in chemotherapy of tumors","volume":"6","author":"M-T Dimanche-Boitrel","year":"2011","journal-title":"Recent Pat Anticancer Drug Discov"},{"issue":"9","key":"pone.0340295.ref033","doi-asserted-by":"crossref","first-page":"911","DOI":"10.2174\/187152011797655177","article-title":"Ceramide-based therapeutics for the treatment of cancer","volume":"11","author":"BM Barth","year":"2011","journal-title":"Anticancer Agents Med Chem"},{"issue":"9","key":"pone.0340295.ref034","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1093\/carcin\/bgv094","article-title":"C6 ceramide dramatically increases vincristine sensitivity both in vivo and in vitro, involving AMP-activated protein kinase-p53 signaling","volume":"36","author":"M-B Chen","year":"2015","journal-title":"Carcinogenesis"},{"issue":"50","key":"pone.0340295.ref035","doi-asserted-by":"crossref","first-page":"6557","DOI":"10.1038\/onc.2010.379","article-title":"Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition","volume":"29","author":"C Ji","year":"2010","journal-title":"Oncogene"},{"issue":"1","key":"pone.0340295.ref036","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.yexcr.2014.12.017","article-title":"C6 ceramide dramatically enhances docetaxel-induced growth inhibition and apoptosis in cultured breast cancer cells: a mechanism study","volume":"332","author":"L Yang","year":"2015","journal-title":"Experimental Cell Research"},{"issue":"1","key":"pone.0340295.ref037","article-title":"C6-ceramide synergistically potentiates the anti-tumor effects of histone deacetylase inhibitors via AKT dephosphorylation and \u03b1-tubulin hyperacetylation both in vitro and in vivo","volume":"2","author":"Q Zhu","year":"2011","journal-title":"Cell Death Dis"},{"issue":"1","key":"pone.0340295.ref038","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.bbrc.2014.08.065","article-title":"C6 ceramide sensitizes pemetrexed-induced apoptosis and cytotoxicity in osteosarcoma cells","volume":"452","author":"X Zhu","year":"2014","journal-title":"Biochem Biophys Res Commun"},{"issue":"15","key":"pone.0340295.ref039","doi-asserted-by":"crossref","first-page":"12960","DOI":"10.1074\/jbc.M110699200","article-title":"Biochemical mechanisms of the generation of endogenous long chain ceramide in response to exogenous short chain ceramide in the A549 human lung adenocarcinoma cell line. Role for endogenous ceramide in mediating the action of exogenous ceramide","volume":"277","author":"B Ogretmen","year":"2002","journal-title":"J Biol Chem"},{"issue":"29","key":"pone.0340295.ref040","doi-asserted-by":"crossref","first-page":"27129","DOI":"10.1074\/jbc.M100729200","article-title":"Activation of a p53-independent, sphingolipid-mediated cytolytic pathway in p53-negative mouse fibroblast cells treated with N-methyl-N-nitro-N-nitrosoguanidine","volume":"276","author":"J Yang","year":"2001","journal-title":"J Biol Chem"},{"key":"pone.0340295.ref041","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/1471-2407-13-151","article-title":"p53-independent early and late apoptosis is mediated by ceramide after exposure of tumor cells to photon or carbon ion irradiation","volume":"13","author":"G Alphonse","year":"2013","journal-title":"BMC Cancer"},{"issue":"8","key":"pone.0340295.ref042","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/sj.cdd.4401428","article-title":"p53-Independent ceramide formation in human glioma cells during gamma-radiation-induced apoptosis","volume":"11","author":"S Hara","year":"2004","journal-title":"Cell Death Differ"},{"issue":"9","key":"pone.0340295.ref043","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1016\/j.cellsig.2010.04.006","article-title":"Ceramide synthases 2, 5, and 6 confer distinct roles in radiation-induced apoptosis in HeLa cells","volume":"22","author":"J Mesicek","year":"2010","journal-title":"Cell Signal"},{"issue":"2","key":"pone.0340295.ref044","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/hep.31304","article-title":"C24\u2010Ceramide Drives Gallbladder Cancer Progression Through Directly Targeting Phosphatidylinositol 5\u2010Phosphate 4\u2010Kinase Type\u20102 Gamma to Facilitate Mammalian Target of Rapamycin Signaling Activation","volume":"73","author":"Y Zhang","year":"2021","journal-title":"Hepatology"},{"issue":"3","key":"pone.0340295.ref045","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s12013-021-00990-1","article-title":"Dihydroceramide Desaturase Functions as an Inducer and Rectifier of Apoptosis: Effect of Retinol Derivatives, Antioxidants and Phenolic Compounds","volume":"79","author":"M Alsanafi","year":"2021","journal-title":"Cell Biochem Biophys"},{"issue":"13","key":"pone.0340295.ref046","doi-asserted-by":"crossref","first-page":"16663","DOI":"10.18632\/oncotarget.7693","article-title":"Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells","volume":"7","author":"M McNaughton","year":"2016","journal-title":"Oncotarget"},{"key":"pone.0340295.ref047","article-title":"Monitoring the Sphingolipid de novo Synthesis by Stable-Isotope Labeling and Liquid Chromatography-Mass Spectrometry","author":"D Wigger","year":"2019","journal-title":"Front Cell Dev Biol [Internet]"},{"issue":"3","key":"pone.0340295.ref048","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1042\/BJ20111626","article-title":"Ceramide synthases at the centre of sphingolipid metabolism and biology","volume":"441","author":"TD Mullen","year":"2012","journal-title":"Biochem J"},{"issue":"7","key":"pone.0340295.ref049","doi-asserted-by":"crossref","first-page":"729","DOI":"10.3390\/medicina57070729","article-title":"Ceramide Metabolism Enzymes-Therapeutic Targets against Cancer","volume":"57","author":"A Gomez-Larrauri","year":"2021","journal-title":"Medicina (Kaunas)"},{"issue":"39","key":"pone.0340295.ref050","doi-asserted-by":"crossref","first-page":"26509","DOI":"10.1074\/jbc.M801597200","article-title":"Ceramide generated by sphingomyelin hydrolysis and the salvage pathway is involved in hypoxia\/reoxygenation-induced Bax redistribution to mitochondria in NT-2 cells","volume":"283","author":"J Jin","year":"2008","journal-title":"J Biol Chem"},{"issue":"2","key":"pone.0340295.ref051","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.plipres.2011.12.002","article-title":"Dihydroceramide desaturase and dihydrosphingolipids: debutant players in the sphingolipid arena","volume":"51","author":"G Fabrias","year":"2012","journal-title":"Prog Lipid Res"},{"issue":"4","key":"pone.0340295.ref052","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1016\/j.bbrc.2008.01.132","article-title":"Sphingosine kinase-1 is a hypoxia-regulated gene that stimulates migration of human endothelial cells","volume":"368","author":"S Schwalm","year":"2008","journal-title":"Biochem Biophys Res Commun"},{"issue":"5","key":"pone.0340295.ref053","doi-asserted-by":"crossref","DOI":"10.1152\/ajpheart.00587.2006","article-title":"Signals from type 1 sphingosine 1-phosphate receptors enhance adult mouse cardiac myocyte survival during hypoxia","volume":"293","author":"J Zhang","year":"2007","journal-title":"Am J Physiol-Heart Circ Physiol"},{"issue":"9","key":"pone.0340295.ref054","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1006\/jmcc.2001.1429","article-title":"The lysophospholipids sphingosine-1-phosphate and lysophosphatidic acid enhance survival during hypoxia in neonatal rat cardiac myocytes","volume":"33","author":"JS Karliner","year":"2001","journal-title":"J Mol Cell Cardiol"},{"issue":"3","key":"pone.0340295.ref055","doi-asserted-by":"crossref","DOI":"10.1038\/oncsis.2016.13","article-title":"Essential role for SphK1\/S1P signaling to regulate hypoxia-inducible factor 2\u03b1 expression and activity in cancer","volume":"5","author":"P Bouquerel","year":"2016","journal-title":"Oncogenesis"},{"issue":"6","key":"pone.0340295.ref056","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.3390\/cells9061379","article-title":"Elusive roles of the different ceramidases in human health, pathophysiology, and tissue regeneration","volume":"9","author":"C Duarte","year":"2020","journal-title":"Cells"},{"key":"pone.0340295.ref057","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.jbior.2016.10.002","article-title":"Ceramidases, roles in sphingolipid metabolism and in health and disease","volume":"63","author":"N Coant","year":"2017","journal-title":"Adv Biol Regul"},{"issue":"2","key":"pone.0340295.ref058","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/jb\/mvj026","article-title":"Apoptosis occurs via the ceramide recycling pathway in human HaCaT keratinocytes","volume":"139","author":"S Takeda","year":"2006","journal-title":"J Biochem"},{"issue":"5","key":"pone.0340295.ref059","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1007\/s00280-010-1374-1","article-title":"C6 ceramide potentiates curcumin-induced cell death and apoptosis in melanoma cell lines in vitro","volume":"66","author":"T Yu","year":"2010","journal-title":"Cancer Chemother Pharmacol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0340295","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T18:49:59Z","timestamp":1767725399000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0340295"}},"subtitle":[],"editor":[{"given":"Herve","family":"Le Stunff","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,1,6]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1,6]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0340295","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,6]]}}}