INHIBITION OF DNA REPAIR FACTORS SENSITIZES HUMAN CANCER CELLS TO SILVER NANOPARTICLES TOXICITY: MECHANISTIC INSIGHTS AND IMPLICATIONS IN CANCER THERAPY

Abstract

Silver nanoparticles (Ag-np) are distinctively reported as toxic agent. This potentially detrimental toxicity of Ag-np can however be used to our advantage to enhance therapeutic efficacy of existing cancer drugs. We found that Ag-np induced more prominent dose-dependent decrease in cell viability in DNA-PKcs deficient or inhibited cells. The deficiency or inhibition of DNA-PKcs renders the cells with higher susceptibility to DNA damage and genome instability which in turn contributed to greater cell cycle arrest/cell death. These findings support the fact that DNA-PKcs is involved in the repair of Ag-np induced DNA damage. At mechanistic level, we found following DNA-PKcs inhibition, JNK pathway was insufficiently activated, abolishing the signalling events required for DNA repair. Localization of activated DNA-PKcs to damaged telomeres indicates the importance of DNA repair machinery at damaged telomeres. DNA-PKcs inhibition substantiates the damaging effect of Ag-np at telomeres in human cancer cells. These two phenomena are responsible for the greater sensitivity of the cancer cells towards Ag-np cytotoxicity. These results suggest inhibition of DNA-PKcs together with Ag-np treatment could be a better strategy to improve anti-proliferative effects in cancer cells.