| Title: |
A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer |
| Authors: |
Dylgjeri, E; Kothari, V; Shafi, AA; Semenova, G; Gallagher, PT; Guan, YF; Pang, A; Goodwin, JF; Irani, S; McCann, JJ; Mandigo, AC; Chand, S; McNair, CM; Vasilevskaya, I; Schiewer, MJ; Lallas, CD; McCue, PA; Gomella, LG; Seifert, EL; Carroll, JS; Butler, LM; Holst, J; Kelly, WK; Knudsen, KE |
| Source: |
urn:ISSN:1078-0432 ; urn:ISSN:1557-3265 ; Clinical Cancer Research, 28, 7, 1446-1459 |
| Publisher Information: |
American Association for Cancer Research (AACR) |
| Publication Year: |
2022 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
32 Biomedical and Clinical Sciences; 3211 Oncology and Carcinogenesis; Genetics; Prostate Cancer; Urologic Diseases; Biotechnology; Cancer; 2.1 Biological and endogenous factors; 5.1 Pharmaceuticals; DNA; DNA-Activated Protein Kinase; Glycolysis; Humans; Male; Prostatic Neoplasms; Castration-Resistant; Proteomics; Pyruvate Kinase; anzsrc-for: 32 Biomedical and Clinical Sciences; anzsrc-for: 3211 Oncology and Carcinogenesis; anzsrc-for: 1112 Oncology and Carcinogenesis; anzsrc-for: 3202 Clinical sciences |
| Description: |
Purpose: DNA-dependent protein 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, and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. Although 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 pharmacologic 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 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 prostate cancer. 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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://hdl.handle.net/1959.4/unsworks_82537 |
| DOI: |
10.1158/1078-0432.CCR-21-1846 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_82537; https://unsworks.unsw.edu.au/bitstreams/85aa5879-0d00-4f0e-89ce-4668ce5ae650/download; https://doi.org/10.1158/1078-0432.CCR-21-1846 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC BY-NC-ND ; https://creativecommons.org/licenses/by-nc-nd/4.0/ ; free_to_read |
| Accession Number: |
edsbas.EF73E8DD |
| Database: |
BASE |