{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:54:23Z","timestamp":1791726863983,"version":"4.3.4"},"reference-count":52,"publisher":"Wiley","license":[{"start":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T00:00:00Z","timestamp":1718323200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K09404"],"award-info":[{"award-number":["21K09404"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K09452"],"award-info":[{"award-number":["22K09452"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K09507"],"award-info":[{"award-number":["22K09507"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K16792"],"award-info":[{"award-number":["22K16792"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K16820"],"award-info":[{"award-number":["22K16820"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"abstract":"<jats:p>\n                    Gemcitabine plus cisplatin (GC) combination chemotherapy is the primary treatment for advanced bladder cancer (BC) with unresectable or metastatic disease. However, most cases develop resistance to this therapy. We investigated whether drug resistance could be targeted through metabolic reprogramming therapies. Metabolomics analyses in our lab's gemcitabine\u2010 and cisplatin\u2010resistant cell lines revealed increased phosphoglycerate dehydrogenase (\n                    <jats:italic>PHGDH<\/jats:italic>\n                    ) expression in gemcitabine\u2010resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia\u2010inducible factor1\u03b1 (\n                    <jats:italic>HIF1\u03b1<\/jats:italic>\n                    ) expression, stimulating aerobic glycolysis. In gemcitabine\u2010resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain\u2010containing protein 2\/Egl nine homolog 1 (\n                    <jats:italic>PHD2<\/jats:italic>\n                    ) and stabilized\n                    <jats:italic>HIF1\u03b1<\/jats:italic>\n                    expression.\n                    <jats:italic>PHGDH<\/jats:italic>\n                    downregulation or inhibition in gemcitabine\u2010resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin\u2010resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (\n                    <jats:italic>FASN<\/jats:italic>\n                    ) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (\n                    <jats:italic>FGFR<\/jats:italic>\n                    ) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl\u2010CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1\u03b1 expression. Combination treatment with NCT503 and erdafitinib synergistically suppressed tumor cell proliferation and induced apoptosis\n                    <jats:italic>in\u2009vitro<\/jats:italic>\n                    and\n                    <jats:italic>in\u2009vivo<\/jats:italic>\n                    . Understanding these mechanisms could enable innovative BC therapeutic strategies to be developed.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13684","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T10:44:21Z","timestamp":1718361861000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeting metabolic reprogramming to overcome drug resistance in advanced bladder cancer: insights from gemcitabine\u2010 and cisplatin\u2010resistant models"],"prefix":"10.1002","author":[{"given":"Ichiro","family":"Kawahara","sequence":"first","affiliation":[{"name":"Department of Urology, Graduate School of Medical and Dental Sciences Kagoshima University  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