| Autor: |
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 |
| Přispěvatelé: |
Carroll, Jason [0000-0003-3643-0080], Apollo - University of Cambridge Repository |
| Rok vydání: |
2022 |
| Předmět: |
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| DOI: |
10.17863/cam.82032 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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