{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T13:20:11Z","timestamp":1765286411428,"version":"3.46.0"},"reference-count":58,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2025,10]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n RT4<\/jats:styled-content>\n bladder cancer cell line, derived from a nonmuscle\u2010invasive low\u2010grade subtype, is one of the few neoplastic cell lineages that maintain high expression of the candidate tumor suppressor\n ALDH1L1<\/jats:styled-content>\n . Here, we investigated how differential\n ALDH1L1<\/jats:styled-content>\n expression affects cellular characteristics and tumorigenicity of\n RT4<\/jats:styled-content>\n cells as well as tumor metabotypes.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We characterized\n RT4<\/jats:styled-content>\n cells and two\n shRNA<\/jats:styled-content>\n clones (sh506\/low\n ALDH1L1<\/jats:styled-content>\n expression; sh572\/\n ALDH1L1<\/jats:styled-content>\n is lost) for proliferation, migration, clonogenic capacity, and mitochondrial respiration. We have further evaluated the tumorigenic potential of\n RT4<\/jats:styled-content>\n cells and the two clones in nude mice and compared metabotypes of derived tumors using untargeted metabolomics.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Both clones with diminished\n ALDH1L1<\/jats:styled-content>\n expression exhibited increased proliferation rates with doubling times of 19.4\u2009h (sh506) and 23.2\u2009h (sh572) versus 36.3\u2009h for\n RT4<\/jats:styled-content>\n cells. Downregulation of\n ALDH1L1<\/jats:styled-content>\n expression also enhanced motility and clonogenic capacity. Proliferation and clonogenic capacity were highest for the sh506 clone (low\n ALDH1L1<\/jats:styled-content>\n expression), while motility was strongest for the sh572 clone (complete\n ALDH1L1<\/jats:styled-content>\n loss). Both clones showed altered energy metabolism, as indicated by a reduced basal oxygen consumption rate and enhanced maximal respiration rate following oligomycin treatment. Mouse xenograft tumors derived from\n ALDH1L1<\/jats:styled-content>\n \u2010deficient\n RT4<\/jats:styled-content>\n clones were significantly larger than\n RT4<\/jats:styled-content>\n cell\u2010derived tumors. Of note, complete\n ALDH1L1<\/jats:styled-content>\n loss (sh572 clone) was less advantageous for tumor growth than the partial loss of the protein (sh506 clone). Untargeted metabolomics has shown that tumors with downregulated\n ALDH1L1<\/jats:styled-content>\n have altered the metabolism of fatty acids, amino acids,\n CoA,<\/jats:styled-content>\n and acylcarnitines. Alterations in several key pathways, including glutathione metabolism (sh506), and\n TCA<\/jats:styled-content>\n cycle (sh572), depend on the extent of\n ALDH1L1<\/jats:styled-content>\n downregulation.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our study underscores\n ALDH1L1<\/jats:styled-content>\n as a key metabolic regulator of proliferation, migration, and tumorigenicity in\n RT4<\/jats:styled-content>\n bladder cancer cells, suggesting that retaining low\n ALDH1L1<\/jats:styled-content>\n expression can provide a metabolic advantage for growth of aggressive tumors.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/cam4.71291","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T12:58:08Z","timestamp":1760101088000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Differential Expression of One\u2010Carbon Pathway Enzyme\n ALDH1L1<\/scp>\n Is Linked to Tumorigenicity of Low\u2010Grade Bladder Cancer Cells Through Metabolic Reprogramming"],"prefix":"10.1002","volume":"14","author":[{"given":"Halle M.","family":"Meyers","sequence":"first","affiliation":[{"name":"Nutrition Research Institute UNC\u2010Chapel Hill Kannapolis North Carolina USA"},{"name":"Department of Nutrition UNC\u2010Chapel Hill Chapel Hill NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaspreet","family":"Sharma","sequence":"additional","affiliation":[{"name":"Nutrition Research Institute UNC\u2010Chapel Hill Kannapolis North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amira A.","family":"Abdellatef","sequence":"additional","affiliation":[{"name":"Nutrition Research Institute UNC\u2010Chapel Hill Kannapolis North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikyoung","family":"You","sequence":"additional","affiliation":[{"name":"Nutrition Research Institute UNC\u2010Chapel Hill Kannapolis North Carolina USA"},{"name":"Department of Food and Nutrition and the Convergence Center for Green Anti\u2010Aging Research Mokpo National University Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Raines","sequence":"additional","affiliation":[{"name":"Nutrition Research Institute UNC\u2010Chapel Hill Kannapolis North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle C.","family":"Strickland","sequence":"additional","affiliation":[{"name":"Labcorp Durham NC USA"},{"name":"Duke University Medical Center, Duke Cancer Institute, Department of Pathology Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Sumner","sequence":"additional","affiliation":[{"name":"Nutrition Research Institute UNC\u2010Chapel Hill Kannapolis North Carolina USA"},{"name":"Department of Nutrition UNC\u2010Chapel Hill Chapel Hill NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blake R.","family":"Rushing","sequence":"additional","affiliation":[{"name":"Nutrition Research Institute UNC\u2010Chapel Hill Kannapolis North Carolina USA"},{"name":"Department of Nutrition UNC\u2010Chapel Hill Chapel Hill NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia I.","family":"Krupenko","sequence":"additional","affiliation":[{"name":"Nutrition Research Institute UNC\u2010Chapel Hill Kannapolis North Carolina USA"},{"name":"Department of Nutrition UNC\u2010Chapel Hill Chapel Hill NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6926-2776","authenticated-orcid":false,"given":"Sergey A.","family":"Krupenko","sequence":"additional","affiliation":[{"name":"Nutrition Research Institute UNC\u2010Chapel Hill Kannapolis North Carolina USA"},{"name":"Department of Nutrition UNC\u2010Chapel Hill Chapel Hill NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph21070954"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2016.06.010"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12965"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euo.2022.05.005"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.24072"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3817"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-12-1150"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64388-X"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-3067"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/jclinpath-2020-207115"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-1065"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.763902"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2016.03.005"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.012809.104810"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.08.009"},{"issue":"5","key":"e_1_2_10_17_1","first-page":"227","article-title":"10\u2010Formyltetrahydrofolate Dehydrogenase, One of the Major Folate Enzymes, Is Down\u2010Regulated in Tumor Tissues and Possesses Suppressor Effects on Cancer Cells","volume":"13","author":"Krupenko S. A.","year":"2002","journal-title":"Cell Growth & Differentiation"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.356"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.5327"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-38142-5"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2008.09.007"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2019.02.013"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00326-0"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-020-03771-1"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-2427"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-012-0123-9"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27238394"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-16-0317"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13133219"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/metabo12050454"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0313159"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24054406"},{"issue":"1","key":"e_1_2_10_33_1","first-page":"1","article-title":"A Systematic Evaluation of Normalization Methods in Quantitative Label\u2010Free Proteomics","volume":"19","author":"V\u00e4likangas T.","year":"2018","journal-title":"Briefings in Bioinformatics"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-018-1367-3"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-007-0082-2"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae253"},{"issue":"8","key":"e_1_2_10_37_1","first-page":"577","article-title":"Ectopic Expression of 10\u2010Formyltetrahydrofolate Dehydrogenase in a549 Cells Induces g(1) Cell Cycle Arrest and Apoptosis","volume":"1","author":"Oleinik N. V.","year":"2003","journal-title":"Molecular Cancer Research"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1177\/1947601911432495"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.461798"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.316"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-05-0243"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2006.04.005"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.118"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2012.07.002"},{"issue":"12","key":"e_1_2_10_46_1","first-page":"1409","article-title":"The Antifolates: Evolution, New Agents in the Clinic, and How Targeting Delivery via Specific Membrane Transporters Is Driving the Development of a Next Generation of Folate Analogs","volume":"11","author":"Goldman I. D.","year":"2010","journal-title":"Current Opinion in Investigational Drugs"},{"issue":"7","key":"e_1_2_10_47_1","first-page":"3630","article-title":"Tissue Culture Model of Transitional Cell Carcinoma: Characterization of Twenty\u2010Two Human Urothelial Cell Lines","volume":"46","author":"Masters J. R.","year":"1986","journal-title":"Cancer Research"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-51397-1"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0182208"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-022-00619-4"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160809"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nox243"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020106491"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005392-199909010-00019"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1080\/03008880802284605"},{"issue":"1","key":"e_1_2_10_56_1","first-page":"31","article-title":"Superficial Bladder Cancer: An Update on Etiology, Molecular Development, Classification, and Natural History","volume":"10","author":"Pasin E.","year":"2008","journal-title":"Revista de Urolog\u00eda"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1080\/03008880802291915"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095-3941.2016.0066"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14020280"}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.71291","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T13:10:31Z","timestamp":1765285831000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.71291"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":58,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/cam4.71291"],"URL":"https:\/\/doi.org\/10.1002\/cam4.71291","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"type":"print","value":"2045-7634"},{"type":"electronic","value":"2045-7634"}],"subject":[],"published":{"date-parts":[[2025,10]]},"assertion":[{"value":"2025-04-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71291"}}