Inhibiting mitochondrial DNA ligase IIIα activates caspase 1-dependent apoptosis in cancer cells

Elevated levels of DNA ligase IIIα (LigIIIα) have been identified as a biomarker of an alteration in DNA repair in cancer cells that confers hypersensitivity to a LigIIIα inhibitor, L67, in combination with a poly (ADP-ribose) polymerase inhibitor. Since LigIIIα functions in the nucleus and mitochondria, we examined the effect of L67 on these organelles. Here we show that, although the DNA ligase inhibitor selectively targets mitochondria, cancer and non-malignant cells respond differently to disruption of mitochondrial DNA metabolism. Inhibition of mitochondrial LigIIIα in cancer cells resulted in abnormal mitochondrial morphology, reduced levels of mitochondrial DNA and increased levels of mitochondrially-generated reactive oxygen species that caused nuclear DNA damage. In contrast, these effects did not occur in non-malignant cells. Furthermore, inhibition of mitochondrial LigIIIα activated a caspase 1-dependent apoptotic pathway that is known to be part of inflammatory responses induced by pathogenic microorganisms in cancer but not non-malignant cells. These results demonstrate that the disruption of mitochondrial DNA metabolism elicits different responses in non-malignant and cancer cells and suggests that the abnormal response in cancer cells may be exploited in the development of novel therapeutic strategies that selectively target cancer cells.