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A novel Chk1-binding peptide that enhances genotoxic sensitivity through the cellular redistribution of nuclear Chk1

  • Authors:
    • Kwang Seok Kim
    • Kyu Jin Choi
    • Sangwoo Bae
  • View Affiliations / Copyright

    Affiliations: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea
    Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1490-1498
    |
    Published online on: September 30, 2016
       https://doi.org/10.3892/ijmm.2016.2762
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Abstract

Since checkpoint kinase 1 (Chk1) is an essential factor for cell viability following DNA damage, the inhibition of Chk1 has been a major focus of pharmaceutical development to enhance the sensitivity of tumor cells to chemo- and radiotherapy that damage DNA. However, due to the off-target effects of conventional Chk1-targeting strategies and the toxicity of Chk1 inhibitors, alternative strategies are required to target Chk1. To facilitate such efforts, in this study, we identified a specific Chk1-binding 12-mer peptide from the screening of a phage display library and characterized the peptide in terms of cellular cytotoxicity, and in terms of its effect on Chk1 activity and sensitivity to genotoxic agents. This peptide, named N-terminal Chk1-binding peptide (Chk1‑NP), bound the kinase domain of Chk1. Simulation of the binding revealed that the very N-terminus of the Chk1 kinase domain is the potential peptide binding site. Of note, the polyarginine-mediated internalization of Chk1‑NP redistributed nuclear Chk1 with a prominent decrease in the nucleus in the absence of DNA damage. Treatment with Chk1‑NP peptide alone decreased the viability of p53-defective HeLa cells, but not that of p53-functional NCI-H460 cells under normal conditions. The treatment of HeLa or NCI-H460 cells with the peptide significantly enhanced radiation sensitivity following ionizing radiation (IR) with a greater enhancement observed in HeLa cells. Moreover, the IR-induced destabilization of Chk1 was aggravated by treatment with Chk1‑NP. Therefore, the decreased nuclear localization and protein levels of Chk1 seem to be responsible for the enhanced cancer cell killing following combined treatment with IR and Chk1‑NP. The approach using the specific Chk1-binding peptide may facilitate the mechanistic understanding and potential modulation of Chk1 activities and may provide a novel rationale for the development of specific Chk1-targeting agents.
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Copy and paste a formatted citation
Spandidos Publications style
Kim KS, Choi KJ and Bae S: A novel Chk1-binding peptide that enhances genotoxic sensitivity through the cellular redistribution of nuclear Chk1. Int J Mol Med 38: 1490-1498, 2016.
APA
Kim, K.S., Choi, K.J., & Bae, S. (2016). A novel Chk1-binding peptide that enhances genotoxic sensitivity through the cellular redistribution of nuclear Chk1. International Journal of Molecular Medicine, 38, 1490-1498. https://doi.org/10.3892/ijmm.2016.2762
MLA
Kim, K. S., Choi, K. J., Bae, S."A novel Chk1-binding peptide that enhances genotoxic sensitivity through the cellular redistribution of nuclear Chk1". International Journal of Molecular Medicine 38.5 (2016): 1490-1498.
Chicago
Kim, K. S., Choi, K. J., Bae, S."A novel Chk1-binding peptide that enhances genotoxic sensitivity through the cellular redistribution of nuclear Chk1". International Journal of Molecular Medicine 38, no. 5 (2016): 1490-1498. https://doi.org/10.3892/ijmm.2016.2762
Copy and paste a formatted citation
x
Spandidos Publications style
Kim KS, Choi KJ and Bae S: A novel Chk1-binding peptide that enhances genotoxic sensitivity through the cellular redistribution of nuclear Chk1. Int J Mol Med 38: 1490-1498, 2016.
APA
Kim, K.S., Choi, K.J., & Bae, S. (2016). A novel Chk1-binding peptide that enhances genotoxic sensitivity through the cellular redistribution of nuclear Chk1. International Journal of Molecular Medicine, 38, 1490-1498. https://doi.org/10.3892/ijmm.2016.2762
MLA
Kim, K. S., Choi, K. J., Bae, S."A novel Chk1-binding peptide that enhances genotoxic sensitivity through the cellular redistribution of nuclear Chk1". International Journal of Molecular Medicine 38.5 (2016): 1490-1498.
Chicago
Kim, K. S., Choi, K. J., Bae, S."A novel Chk1-binding peptide that enhances genotoxic sensitivity through the cellular redistribution of nuclear Chk1". International Journal of Molecular Medicine 38, no. 5 (2016): 1490-1498. https://doi.org/10.3892/ijmm.2016.2762
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