A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration Resistant Prostate Cancer.
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Authors
Dylgjeri, Emanuela
Kothari, Vishal
Shafi, Ayesha A
Semenova, Galina
Gallagher, Peter T
Guan, Yi Fang
Pang, Angel
Goodwin, Jonathan F
Irani, Swati
McCann, Jennifer J
Mandigo, Amy C
Chand, Saswati
McNair, Christopher M
Vasilevskaya, Irina
Schiewer, Matthew J
Lallas, Costas D
McCue, Peter A
Gomella, Leonard G
Seifert, Erin L
Carroll, Jason S
Butler, Lisa M
Holst, Jeff
Kelly, William K
Knudsen, Karen E
Publication Date
2022-01-25Journal Title
Clinical Cancer Research
ISSN
1078-0432
Publisher
American Association for Cancer Research
Pages
clincanres.1846.2021-clincanres.1846.2021
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Dylgjeri, E., Kothari, V., Shafi, A. A., Semenova, G., Gallagher, P. T., Guan, Y. F., Pang, A., et al. (2022). A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration Resistant Prostate Cancer.. Clinical Cancer Research, clincanres.1846.2021-clincanres.1846.2021. https://doi.org/10.1158/1078-0432.CCR-21-1846
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.
Sponsorship
Cancer Research UK (C14303/A17197)
Cancer Research UK (C9545/A29580_do not transfer)
Identifiers
External DOI: https://doi.org/10.1158/1078-0432.CCR-21-1846
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334613
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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