title: Inhibiting Mitochondrial DNA Ligase IIIα Activates Caspase 1-Dependent Apoptosis in Cancer Cells.
abstract: 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. Because 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 nonmalignant 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 nonmalignant cells. Furthermore, inhibition of mitochondrial LigIIIα activated a caspase 1-dependent apoptotic pathway, which is known to be part of inflammatory responses induced by pathogenic microorganisms in cancer, but not nonmalignant cells. These results demonstrate that the disruption of mitochondrial DNA metabolism elicits different responses in nonmalignant 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. Cancer Res; 76(18); 5431-41. ©2016 AACR.
authors: Departments of Internal Medicine and Molecular Genetics and Microbiology, and University of New Mexico Cancer Center, University of New Mexico, Albuquerque, New Mexico.
authors: Annahita
authors: A
authors: Sallmyr
authors: Departments of Internal Medicine and Molecular Genetics and Microbiology, and University of New Mexico Cancer Center, University of New Mexico, Albuquerque, New Mexico.
authors: Yoshihiro
authors: Y
authors: Matsumoto
authors: Department of Pharmacology and Cell Biology, University of Pittsburgh School of Medicine and The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania.
authors: Vera
authors: V
authors: Roginskaya
authors: Department of Pharmacology and Cell Biology, University of Pittsburgh School of Medicine and The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania.
authors: Bennett
authors: B
authors: Van Houten
authors: Departments of Internal Medicine and Molecular Genetics and Microbiology, and University of New Mexico Cancer Center, University of New Mexico, Albuquerque, New Mexico. atomkinson@salud.unm.edu.
authors: Alan E
authors: AE
authors: Tomkinson
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D000075223:Poly-ADP-Ribose Binding Proteins; D029867:Xenopus Proteins
chemical_list: D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; D000075223:Poly-ADP-Ribose Binding Proteins; D029867:Xenopus Proteins; D020170:Caspase 1; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus