Bavachalcone targets TFRC and sensitizes gemcitabine to affect bladder cancer progression through the iron-dependent ATR-CHEK1-E2F1 signaling pathway

Bavachalcone targets TFRC and sensitizes gemcitabine to affect bladder cancer progression through the iron-dependent ATR-CHEK1-E2F1 signaling pathway | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Bavachalcone targets TFRC and sensitizes gemcitabine to affect bladder cancer progression through the iron-dependent ATR-CHEK1-E2F1 signaling pathway Zihao Zhang, Chenyue Yuan, Qintao Ge, Wangrui Liu, Meng Xu, Mengfei Wang, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5823613/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Gemcitabine resistance is a critical factor contributing to the recurrence and progression of bladder cancer. In this study, we utilized high-throughput drug screening and bladder cancer organoid models to identify Bavachalcone (Bava) as a sensitizing agent for gemcitabine, thereby inhibiting the progression of bladder cancer. Bava targets transferrin receptor (TFRC) and epidermal growth factor receptor (EGFR), competitively binding to TFRC with transferrin (Tf), which reduces the influx of iron ions and the activity of mitochondrial respiratory chain complexes. Concurrently, Bava inhibits the phosphorylation of TFRC at tyrosine 20 (Y20) by blocking EGFR phosphorylation, thereby stabilizing TFRC on the cell membrane. The combination of Bava and gemcitabine effectively inhibits the repair of DNA damage induced by gemcitabine. Additionally, Bava suppresses the iron-induced ATR-CHEK1-E2F1 signaling pathway and decreases the expression of RRM1, further sensitizing cells to gemcitabine. Studies utilizing patient-derived xenografts of bladder cancer have demonstrated that the Bava-gemcitabine combination significantly inhibits tumor progression. Correlating with clinical data, we found that TFRC and RRM1 may serve as markers of poor prognosis in bladder cancer. In summary, our research has identified specific Chinese medicine monomers that sensitize cells to gemcitabine, elucidated their direct action targets, and highlighted the role of iron ions in tumor development. This work also paves the way for novel drug design strategies that target TFRC to inhibit iron ion influx and mitigate bladder cancer progression. Bladder cancer Gemcitabine resistance Bavachalcone DNA damage repair TFRC and RRM1 Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementalTable1.pdf SupplementalTable2.pdf SupplementalTable3RNAseq.xlsx SupplementalTable4Massspectrometry.xlsx SupplementalTable5Drugtestreport.pdf SupplementalTable6CellSPR.pdf SupportingInformation.pdf DetailedMethods.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5823613","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":401820157,"identity":"87ee2a8f-8853-46d5-aea5-0397e7a93a75","order_by":0,"name":"Zihao 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pathway","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Bladder cancer, Gemcitabine resistance, Bavachalcone, DNA damage repair, TFRC and RRM1","lastPublishedDoi":"10.21203/rs.3.rs-5823613/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5823613/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Gemcitabine resistance is a critical factor contributing to the recurrence and progression of bladder cancer. In this study, we utilized high-throughput drug screening and bladder cancer organoid models to identify Bavachalcone (Bava) as a sensitizing agent for gemcitabine, thereby inhibiting the progression of bladder cancer. Bava targets transferrin receptor (TFRC) and epidermal growth factor receptor (EGFR), competitively binding to TFRC with transferrin (Tf), which reduces the influx of iron ions and the activity of mitochondrial respiratory chain complexes. Concurrently, Bava inhibits the phosphorylation of TFRC at tyrosine 20 (Y20) by blocking EGFR phosphorylation, thereby stabilizing TFRC on the cell membrane. The combination of Bava and gemcitabine effectively inhibits the repair of DNA damage induced by gemcitabine. Additionally, Bava suppresses the iron-induced ATR-CHEK1-E2F1 signaling pathway and decreases the expression of RRM1, further sensitizing cells to gemcitabine. Studies utilizing patient-derived xenografts of bladder cancer have demonstrated that the Bava-gemcitabine combination significantly inhibits tumor progression. Correlating with clinical data, we found that TFRC and RRM1 may serve as markers of poor prognosis in bladder cancer. In summary, our research has identified specific Chinese medicine monomers that sensitize cells to gemcitabine, elucidated their direct action targets, and highlighted the role of iron ions in tumor development. This work also paves the way for novel drug design strategies that target TFRC to inhibit iron ion influx and mitigate bladder cancer progression.","manuscriptTitle":"Bavachalcone targets TFRC and sensitizes gemcitabine to affect bladder cancer progression through the iron-dependent ATR-CHEK1-E2F1 signaling pathway","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-15 15:20:46","doi":"10.21203/rs.3.rs-5823613/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6b826825-f965-4660-9a74-4ef20d484690","owner":[],"postedDate":"January 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-15T17:23:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-15 15:20:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5823613","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5823613","identity":"rs-5823613","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}