Mitochondrial alteration in malignantly transformed human small airway epithelial cells induced by α-particles.
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.
Center for Radiological Research, College of Physicians and Surgeons, Columbia University Medical Center, New York 10032, USA.
Suping
S
Zhang
Gengyun
G
Wen
Sarah X L
SX
Huang
Jianrong
J
Wang
Jian
J
Tong
Tom K
TK
Hei
D000512:Alpha Particles; D000818:Animals; D001216:Asparagine / Q000031:analogs & derivatives / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects*; D063065:Organophosphonates / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism
D004272:DNA, Mitochondrial; C514368:N-phoshponacetylisoasparagine; D063065:Organophosphonates; D016271:Proto-Oncogene Proteins c-myc; D001216:Asparagine; D003576:Electron Transport Complex IV