Mitochondrial alteration in malignantly transformed human small airway epithelial cells induced by α-particles

Abstract

Human small airway epithelial cells (SAECs) immortalized with human telomerase reverse transcriptase were exposed to either a single or multiple doses of α-particles. Irradiated cells showed a dose-dependent cytotoxicity and progressive neoplastic transformation phenotype. These included an increase in saturation density of growth, a greater resistance to N-phosphonoacetyl-L-aspartate, faster anchorage-independent growth, reinforced cell invasion and c-Myc expression. In addition, the transformed cells formed progressively growing tumors upon inoculation into athymic nude mice. Specifically, α-irradiation induced damage to both mitochondrial DNA (mtDNA) and mitochondrial functions in transformed cells as evidenced by increased mtDNA copy number and common deletion, decreased oxidative phosphorylation activity as measured by cytochrome C oxidase (COX) activity and oxygen consumption. There was a linear correlation between mtDNA copy number, common deletion, COX activity and cellular transformation represented by soft agar colony formation and c-Myc expression. These results suggest that mitochondria are associated with neoplastic transformation of SAEC cells induced by α-particles, and that the oncogenesis process may depend not only on the genomes inside the nucleus, but also on the mitochondrial DNA outside the nucleus. What's new? Even a single dose of radiation in the form of alpha particles can bring on cancer by damaging DNA. Originally, it was assumed that the particles caused cancer by mutating nuclear DNA, but some recent studies have showed that they may wreak their chaos on mitochondrial DNA, as well. In this study, the authors investigated the effect of alpha particles on immortalized small airway epithelial cells. They immortalized these cells using human telomerase reverse transcriptase, a better model for studying intracellular molecular pathways, which can be altered by viral methods of immortalizing cells. Cells that had been transformed by exposure to alpha particles showed damage to mitochondrial DNA, suggesting there may be more paths to cancer than previously thought. Copyright © 2012 UICC.