DNA-dependent protein kinase modulates the anti-cancer properties of silver nanoparticles in human cancer cells

Abstract

Silver nanoparticles (Ag-np) were reported to be toxic to eukaryotic cells. These potentially detrimental effects of Ag-np can be advantageous in experimental therapeutics. They are currently being employed to enhance the therapeutic efficacy of cancer drugs. In this study, we demonstrate that Ag-np treatment trigger the activation of DNA-PKcs and JNK pathway at selected doses, presumably as a physiologic response to DNA damage and repair in normal and malignant cells. Ag-np altered the telomere dynamics by disrupting the shelterin complex located at the telomeres and telomere lengths. The genotoxic effect of Ag-np was not restricted to telomeres but the entire genome as Ag-np induced γ-H2AX foci formation, an indicator of global DNA damage. Inhibition of DNA-PKcs activity sensitised the cancer cells towards the cytotoxicity of Ag-np and substantiated the damaging effect of Ag-np at telomeres in human cancer cells. Abrogation of JNK mediated DNA repair and extensive damage of telomeres led to greater cell death following Ag-np treatment in DNA-PKcs inhibited cancer cells. Collectively, this study suggests that improved anti-proliferative and cytotoxic effects of Ag-np treatment in cancer cells can be achieved by the inhibition of DNA-PKcs.

Keywords: Anti-cancer effects; DNA damage; DNA repair; DNA-PKcs; JNK; Silver nanoparticles; Telomeres.