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Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Kancera AB, Sweden.
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Rekke forfattare: 212018 (engelsk)Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikkel-id 3872Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anticancer 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-gamma H2AX-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.

sted, utgiver, år, opplag, sider
2018. Vol. 9, artikkel-id 3872
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Identifikatorer
URN: urn:nbn:se:su:diva-161195DOI: 10.1038/s41467-018-06287-xISI: 000445329000007PubMedID: 30250201OAI: oai:DiVA.org:su-161195DiVA, id: diva2:1259980
Tilgjengelig fra: 2018-10-31 Laget: 2018-10-31 Sist oppdatert: 2018-10-31bibliografisk kontrollert

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