A Targeted Inhibition of DNA-Dependent Protein Kinase Sensitizes Breast Cancer Cells Following Ionizing Radiation

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Abstract
A major mechanism by which cancer cells become resistant to ionizing radiation (IR) and chemotherapy drugs is by enhanced DNA repair of the lesions; therefore, through inhibition of DNA repair pathways that tumor cells rely on to escape chemotherapy, we expect to increase the killing of cancer cells and reduce drug resistance. DNA-dependent protein kinase (DNA-PK) is a nuclear serine/threonine protein kinase essential for DNA repair as well as sensing and transmitting a damage signal to downstream targets leading to cell cycle arrest. We used a peptide cotherapy strategy to see whether a targeted inhibition of DNA-PK activity sensitizes breast cancer cells in response to IR or chemotherapy drug. A synthesized peptide representing the C terminus of Ku80 (HNI-38) selectively targeted and disrupted interaction between Ku complex and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) as well as the DNA binding activity of Ku that led to the inhibition of DNA-PK activity and reduction in double-stranded DNA break (dsb) repair activity. Furthermore, a peptide-based inhibitor with target sequence effectively inhibited the growth of breast cancer cells only in the presence of DNA damage, suggesting that the target peptide sensitizes cancer cells through blocking dsb DNA repair activity. Together, this study not only validates the involvement of the C terminus of Ku80 in Ku's DNA termini binding and interaction with DNA-PKcs, but also a supports physiological role for DNA-PK in IR or chemotherapy drug resistance of cancer cells.