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Supplementary Figure from A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer

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posted on 2023-03-31, 23:16 authored by Emanuela Dylgjeri, Vishal Kothari, Ayesha A. Shafi, Galina Semenova, Peter T. Gallagher, Yi F. Guan, Angel Pang, Jonathan F. Goodwin, Swati Irani, Jennifer J. McCann, Amy C. Mandigo, Saswati Chand, Christopher M. McNair, Irina Vasilevskaya, Matthew J. Schiewer, Costas D. Lallas, Peter A. McCue, Leonard G. Gomella, Erin L. Seifert, Jason S. Carroll, Lisa M. Butler, Jeff Holst, William K. Kelly, Karen E. Knudsen
Supplementary Figure from A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer

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NIH

NCI

Sidney Kimmel Cancer Center

Prostate Cancer Foundation Young Investigator Award

Tour de Cure Senior Research Grant

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ARTICLE ABSTRACT

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. 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). 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. 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.

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