Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination
| Autor: | Jessica Hollers, Martin Norin, Katarina Färnegårdh, Jemina Lehto, Nadilly Bonagas, N. Markova, Carina Norström, Anna Huguet Ninou, Petra Groth, Nina M. S. Gustafsson, Martin Andersson, Jessica Martinsson, Baek Kim, Elisee Wiita, Rosa Pennisi, Thomas Olin, Kenth Hallberg, Johan Schultz, Mattias Jönsson, Petra Marttila, Thomas Helleday |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell Survival Phosphofructokinase-2 DNA damage DNA repair Science General Physics and Astronomy Antineoplastic Agents Radiation Tolerance General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound Cell Line Tumor Neoplasms Radiation Ionizing Hydroxybenzoates medicine Humans DNA Breaks Double-Stranded Sulfones Enzyme Inhibitors RNA Small Interfering lcsh:Science chemistry.chemical_classification Multidisciplinary Biphenyl Compounds Recombinational DNA Repair Cancer Chemoradiotherapy General Chemistry medicine.disease Small molecule 3. Good health Cell biology 030104 developmental biology Enzyme chemistry Cancer cell lcsh:Q Homologous recombination DNA Dideoxynucleotides |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-16 (2018) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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