방사선생물학

  • [Nat Commun.] Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination.

    University of Sheffield / Helleday T*

  • 출처
    Nat Commun.
  • 등재일
    2018 Sep 24
  • 저널이슈번호
    9(1):3872. doi: 10.1038/s41467-018-06287-x.
  • 내용

    바로가기  >

    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.

     


    Author information

    Gustafsson NMS1,2, Färnegårdh K3,4, Bonagas N5, Ninou AH5,3, Groth P5, Wiita E5, Jönsson M3, Hallberg K6,7, Lehto J5,3, Pennisi R8, Martinsson J7, Norström C3, Hollers J9, Schultz J3, Andersson M7, Markova N10, Marttila P5, Kim B9,11, Norin M3, Olin T3, Helleday T12,13.
    1
    Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, 171 21, Stockholm, Sweden. nina.gustafsson@scilifelab.se.
    2
    Kancera AB, Karolinska Science Park, 171 48, Solna, Sweden. nina.gustafsson@scilifelab.se.
    3
    Kancera AB, Karolinska Science Park, 171 48, Solna, Sweden.
    4
    Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Box 1030, S-171 21, Solna, Sweden.
    5
    Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, 171 21, Stockholm, Sweden.
    6
    SARomics Biostructures AB, Medicon Village, SE-223 81, Lund, Sweden.
    7
    Sprint Bioscience, 141 57, Huddinge, Sweden.
    8
    Department of Sciences, Roma Tre University, 446 00146 Rome, Italy.
    9
    Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
    10
    Malvern Instruments, 752 28, Uppsala, Sweden.
    11
    Department of Pharmacy, Kyung-Hee University, 02447, Seoul, South Korea.
    12
    Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, 171 21, Stockholm, Sweden. t.helleday@sheffield.ac.uk.
    13
    Sheffield Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, S10 2RX, Sheffield, UK. t.helleday@sheffield.ac.uk.

  • 편집위원

    Glycolytic PFKFB3는 다양한 cancer cells에서 과발현되는 항암치료의 표적이다. 본 연구에서는 PFKFB3가 IR에 의해 핵으로 이동하여 DNA double-strand breaks의 HR(homologous recombination) repair에 관여함을 밝혔다. 또한 small molecular inhibitor인 KAN0438757을 발굴하여, PFKFB3의 저해가 repair 과정에서 ribonucleotide reductase M2와 deoxynucleotide의 incorporation을 억제함으로써 cancer의 방사선민감성을 증대시킴을 규명하였다.

    2018-10-22 18:53:09

  • 덧글달기
    덧글달기
       IP : 44.192.253.106

    등록