A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration Resistant Prostate Cancer.
dc.contributor.author | Dylgjeri, Emanuela | |
dc.contributor.author | Kothari, Vishal | |
dc.contributor.author | Shafi, Ayesha A | |
dc.contributor.author | Semenova, Galina | |
dc.contributor.author | Gallagher, Peter T | |
dc.contributor.author | Guan, Yi Fang | |
dc.contributor.author | Pang, Angel | |
dc.contributor.author | Goodwin, Jonathan F | |
dc.contributor.author | Irani, Swati | |
dc.contributor.author | McCann, Jennifer J | |
dc.contributor.author | Mandigo, Amy C | |
dc.contributor.author | Chand, Saswati | |
dc.contributor.author | McNair, Christopher M | |
dc.contributor.author | Vasilevskaya, Irina | |
dc.contributor.author | Schiewer, Matthew J | |
dc.contributor.author | Lallas, Costas D | |
dc.contributor.author | McCue, Peter A | |
dc.contributor.author | Gomella, Leonard G | |
dc.contributor.author | Seifert, Erin L | |
dc.contributor.author | Carroll, Jason | |
dc.contributor.author | Butler, Lisa M | |
dc.contributor.author | Holst, Jeff | |
dc.contributor.author | Kelly, William K | |
dc.contributor.author | Knudsen, Karen E | |
dc.date.accessioned | 2022-03-03T00:30:43Z | |
dc.date.available | 2022-03-03T00:30:43Z | |
dc.date.issued | 2022-01-25 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://www.repository.cam.ac.uk/handle/1810/334613 | |
dc.description.abstract | PURPOSE: 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.medium | Print-Electronic | |
dc.publisher | American Association for Cancer Research | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.title | A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration Resistant Prostate Cancer. | |
dc.type | Article | |
dc.publisher.department | Department of Oncology | |
dc.date.updated | 2022-03-02T14:04:37Z | |
prism.endingPage | clincanres.1846.2021 | |
prism.publicationDate | 2022 | |
prism.publicationName | Clinical Cancer Research | |
prism.startingPage | clincanres.1846.2021 | |
dc.identifier.doi | 10.17863/CAM.82032 | |
dcterms.dateAccepted | 2022-01-20 | |
rioxxterms.versionofrecord | 10.1158/1078-0432.CCR-21-1846 | |
rioxxterms.version | VoR | |
dc.contributor.orcid | Carroll, Jason [0000-0003-3643-0080] | |
dc.identifier.eissn | 1557-3265 | |
rioxxterms.type | Journal Article/Review | |
pubs.funder-project-id | Cancer Research UK (C14303/A17197) | |
pubs.funder-project-id | Cancer Research UK (C9545/A29580_do not transfer) | |
cam.issuedOnline | 2022-01-24 | |
cam.depositDate | 2022-03-02 | |
pubs.licence-identifier | apollo-deposit-licence-2-1 | |
pubs.licence-display-name | Apollo Repository Deposit Licence Agreement |
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