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Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination
- Source :
- Nature Communications, Vol 9, Iss 1, Pp 1-16 (2018), Nature Communications
- Publication Year :
- 2018
- Publisher :
- Nature Research, 2018.
-
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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Database :
- OpenAIRE
- Journal :
- Nature Communications, Vol 9, Iss 1, Pp 1-16 (2018), Nature Communications
- Accession number :
- edsair.doi.dedup.....a7ea467c334b76d93f503c7eee3f7fb8