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  • [Int J Mol Sci.] Checkpoint Kinase 1 (CHK1) Inhibition Enhances the Sensitivity of Triple-Negative Breast Cancer Cells to Proton Irradiation via Rad51 Downregulation.

    성균관의대 / 최창훈, 조원경, 최두호*

  • 출처
    Int J Mol Sci.
  • 등재일
    2020 Apr 13
  • 저널이슈번호
    21(8). pii: E2691. doi: 10.3390/ijms21082691.
  • 내용

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    Abstract
    Due to a superior dose conformity to the target, proton beam therapy (PBT) continues to rise in popularity. Recently, considerable efforts have been directed toward discovering treatment options for use in combination with PBT. This study aimed to investigate the targeting of checkpoint kinase 1 (CHK1), a critical player regulating the G2/M checkpoint, as a promising strategy to potentiate PBT in human triple-negative breast cancer (TNBC) cells. Protons induced cell-cycle arrest at the G2/M checkpoint more readily in response to increased CHK1 activation than X-rays. A clonogenic survival assay revealed that CHK1 inhibition using PF-477736 or small interfering RNA (siRNA) enhanced the sensitivity toward protons to a greater extent than toward X-rays. Western blotting demonstrated that PF-477736 treatment in the background of proton irradiation increased the pro-apoptotic signaling, which was further supported by flow cytometry using annexin V. Immunofluorescence revealed that proton-induced DNA double-strand breaks (DSBs) were further enhanced by PF-477736, which was linked to the downregulation of Rad51, essential for the homologous recombination repair of DSBs. Direct inactivation of Rad51 resulted in enhanced proton sensitization. Collectively, these data suggest that targeting CHK1 may be a promising approach for improving PBT efficacy in the treatment of TNBC.

     


    Author information

    Choi C1, Cho WK1, Park S1, Shin SW1,2, Park W1,2, Kim H1,2, Choi DH1,2.
    1
    Department of Radiation Oncology, Samsung Medical Center, Seoul 06351, Korea.
    2
    Department of Radiation Oncology, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.

  • 키워드
    CHK1; Rad51; proton therapy; triple-negative breast cancer
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