{"doi":"10.1158/1078-0432.c.6531392","title":"Data from A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer","abstract":"<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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 <i>in vitro</i> cell models, <i>in vivo</i> xenografts, and <i>ex vivo</i> in patient-derived explants (PDE).</p>Results:<p>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 (<i>in vitro</i>), 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 <i>in vitro</i>, <i>in vivo</i>, and <i>ex vivo</i>; and (vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease.</p>Conclusions:<p>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.</p></div>","journal":null,"year":2023,"id":405670,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":304681,"name":"Vishal Kothari","orcid":"0000-0002-3612-8810","position":1,"is_corresponding":false},{"id":637843,"name":"Ayesha A. Shafi","orcid":"0000-0003-0335-638X","position":2,"is_corresponding":false},{"id":257410,"name":"Galina Semenova","orcid":null,"position":3,"is_corresponding":false},{"id":1184245,"name":"P. T. Gallagher","orcid":"0000-0001-9745-0400","position":4,"is_corresponding":false},{"id":573711,"name":"Yi Fang Guan","orcid":"0000-0003-4031-8948","position":5,"is_corresponding":false},{"id":573710,"name":"Angel Pang","orcid":"0000-0003-1001-5102","position":6,"is_corresponding":false},{"id":896779,"name":"Jonathan F. Goodwin","orcid":null,"position":7,"is_corresponding":false},{"id":896780,"name":"Swati Irani","orcid":null,"position":8,"is_corresponding":false},{"id":580220,"name":"Jennifer J. McCann","orcid":"0000-0003-4956-1880","position":9,"is_corresponding":false},{"id":573708,"name":"Amy C. Mandigo","orcid":"0000-0003-4683-5268","position":10,"is_corresponding":false},{"id":637847,"name":"Saswati N. Chand","orcid":"0000-0001-5625-0517","position":11,"is_corresponding":false},{"id":573709,"name":"Christopher McNair","orcid":"0000-0003-3204-8482","position":12,"is_corresponding":false},{"id":580219,"name":"Irina A. Vasilevskaya","orcid":"0000-0001-7550-5001","position":13,"is_corresponding":false},{"id":637848,"name":"Matthew J. Schiewer","orcid":"0000-0002-2325-4228","position":14,"is_corresponding":false},{"id":529080,"name":"Costas D. Lallas","orcid":"0000-0001-8937-7661","position":15,"is_corresponding":false},{"id":292750,"name":"Peter A. McCue","orcid":"0000-0001-9806-0594","position":16,"is_corresponding":false},{"id":465012,"name":"Leonard G. Gomella","orcid":"0000-0002-9466-489X","position":17,"is_corresponding":false},{"id":261603,"name":"Erin L. Seifert","orcid":null,"position":18,"is_corresponding":false},{"id":249329,"name":"Jason S. Carroll","orcid":"0000-0003-3643-0080","position":19,"is_corresponding":false},{"id":109885,"name":"Lisa M. Butler","orcid":"0000-0003-2698-3220","position":20,"is_corresponding":false},{"id":573712,"name":"Jeff Holst","orcid":"0000-0002-0377-9318","position":21,"is_corresponding":false},{"id":529878,"name":"William Kevin Kelly","orcid":null,"position":22,"is_corresponding":false},{"id":573713,"name":"Karen E. Knudsen","orcid":"0000-0002-1301-890X","position":23,"is_corresponding":false},{"id":637846,"name":"Emanuela Dylgjeri","orcid":"0000-0002-1784-634X","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T01:20:54.430249Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}