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dc.contributor.authorDylgjeri, Emanuela
dc.contributor.authorKothari, Vishal
dc.contributor.authorShafi, Ayesha A
dc.contributor.authorSemenova, Galina
dc.contributor.authorGallagher, Peter T
dc.contributor.authorGuan, Yi Fang
dc.contributor.authorPang, Angel
dc.contributor.authorGoodwin, Jonathan F
dc.contributor.authorIrani, Swati
dc.contributor.authorMcCann, Jennifer J
dc.contributor.authorMandigo, Amy C
dc.contributor.authorChand, Saswati
dc.contributor.authorMcNair, Christopher M
dc.contributor.authorVasilevskaya, Irina
dc.contributor.authorSchiewer, Matthew J
dc.contributor.authorLallas, Costas D
dc.contributor.authorMcCue, Peter A
dc.contributor.authorGomella, Leonard G
dc.contributor.authorSeifert, Erin L
dc.contributor.authorCarroll, Jason
dc.contributor.authorButler, Lisa M
dc.contributor.authorHolst, Jeff
dc.contributor.authorKelly, William K
dc.contributor.authorKnudsen, Karen E
dc.date.accessioned2022-03-03T00:30:43Z
dc.date.available2022-03-03T00:30:43Z
dc.date.issued2022-01-25
dc.identifier.issn1078-0432
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/334613
dc.description.abstractPURPOSE: DNA-dependent kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer (PCa), and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. While DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes. EXPERIMENTAL DESIGN: Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacological and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE). RESULTS: Key findings reveal: i) the first-in-field DNA-PK protein-protein interactome; ii) numerous DNA-PK novel partners involved in glycolysis, iii) DNA-PK interacts with, phosphorylates (in vitro) and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2, iv) DNA-PK drives synthesis of glucose-derived pyruvate and lactate, v) DNA-PK regulates glycolysis in vitro, in vivo and ex vivo, and vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease. CONCLUSIONS: Findings herein unveil novel DNA-PK partners, substrates, and function in PCa. The role of DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK-mediated aggressive disease phenotypes.
dc.format.mediumPrint-Electronic
dc.publisherAmerican Association for Cancer Research
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleA Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration Resistant Prostate Cancer.
dc.typeArticle
dc.publisher.departmentDepartment of Oncology
dc.date.updated2022-03-02T14:04:37Z
prism.endingPageclincanres.1846.2021
prism.publicationDate2022
prism.publicationNameClinical Cancer Research
prism.startingPageclincanres.1846.2021
dc.identifier.doi10.17863/CAM.82032
dcterms.dateAccepted2022-01-20
rioxxterms.versionofrecord10.1158/1078-0432.CCR-21-1846
rioxxterms.versionVoR
dc.contributor.orcidCarroll, Jason [0000-0003-3643-0080]
dc.identifier.eissn1557-3265
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCancer Research UK (C14303/A17197)
pubs.funder-project-idCancer Research UK (C9545/A29580_do not transfer)
cam.issuedOnline2022-01-24
cam.depositDate2022-03-02
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International