1. Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination.
- Author
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Gustafsson NMS, Färnegårdh K, Bonagas N, Ninou AH, Groth P, Wiita E, Jönsson M, Hallberg K, Lehto J, Pennisi R, Martinsson J, Norström C, Hollers J, Schultz J, Andersson M, Markova N, Marttila P, Kim B, Norin M, Olin T, and Helleday T
- Subjects
- Antineoplastic Agents therapeutic use, Biphenyl Compounds therapeutic use, Cell Line, Tumor, Cell Survival drug effects, Cell Survival radiation effects, Chemoradiotherapy methods, DNA Breaks, Double-Stranded radiation effects, Dideoxynucleotides metabolism, Enzyme Inhibitors therapeutic use, Humans, Hydroxybenzoates therapeutic use, Phosphofructokinase-2 genetics, Phosphofructokinase-2 metabolism, RNA, Small Interfering metabolism, Radiation Tolerance drug effects, Radiation Tolerance genetics, Radiation, Ionizing, Recombinational DNA Repair drug effects, Recombinational DNA Repair radiation effects, Sulfones therapeutic use, Antineoplastic Agents pharmacology, Biphenyl Compounds pharmacology, Enzyme Inhibitors pharmacology, Hydroxybenzoates pharmacology, Neoplasms therapy, Phosphofructokinase-2 antagonists & inhibitors, Sulfones pharmacology
- Abstract
The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anti-cancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-γH2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.
- Published
- 2018
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