Depletion of mitochondrial DNA and enzyme in estrogen-induced hamster kidney tumors: a rodent model of hormonal carcinogenesis.
Mitochondrial DNA (mtDNA) encodes for 13 polypeptides critical for normal functioning of the electron transport chain and damage to mtDNA has been associated with aging, and implicated in several disease processes. Although damage to mtDNA is being implicated in mutagenesis and carcinogenesis, there are limited studies demonstrating the role and extent of mtDNA damage in human or rodent cancers. Using serial dilution and competitive polymerase chain reaction analysis, we have quantitated the amount of total mtDNA and analyzed the extent of mtDNA damage in estrogen-induced and estrogen-dependent hamster kidney tumors. The hamster kidney tumor model is a useful and widely investigated rodent model of hormonal carcinogenesis, which shares several characteristics with human breast and uterine cancers, and point to a common mechanistic pathway. Our data indicate a significant decrease in the copy number of total mtDNA and the activity of a nuclear-encoded mitochondrial enzyme citrate synthase in hamster kidney tumors compared to age-matched controls. Since there are several hundred mitochondria in a cell and each mitochondrion has multiple copies of mtDNA, a very small percentage of somatic deletion mutation may not be enough to result in a decreased capacity of the mitochondrial genome. However, a significant increase in deletion mutations or a decrease in the mtDNA copy number can result in a decreased oxidative phosphorylation capacity of the mitochondria and decreased energetics, and thus increased susceptibility to the disease process. Therefore, estrogen-induced hamster kidney tumor model can be a useful rodent model of carcinogenesis to understand the role of mtDNA damage in cancer progression and development.
Bhat
Hari K
HK
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA. hb2009@columbia.edu
D000818:Animals; D001483:Base Sequence; D002950:Citrate (si)-Synthase / Q000378:metabolism; D006224:Cricetinae; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics*; D004195:Disease Models, Animal; D004958:Estradiol / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008647:Mesocricetus; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
D004272:DNA, Mitochondrial; D004958:Estradiol; D002950:Citrate (si)-Synthase