Differential proliferative responses of Syrian hamster embryo fibroblasts to paraquat-generated superoxide radicals depending on tumor suppressor gene function.
Oxygen radicals have been widely implicated in neoplastic transformation; however, little is known regarding their mode of action. In an attempt to delineate potential mechanisms of action, an analysis of superoxide effects on cell growth was studied in normal and two nontumorigenic, immortal cell lines derived from normal Syrian hamster embryo (SHE) fibroblasts. The two immortal cell lines differed in their ability to suppress tumorigenicity of tumor cells in cell hybrids. One cell line suppressed tumorigenicity (sup+), while a second clone was unable to suppress tumorigenicity (sup-). Paraquat was used to generate superoxide through its capacity to be reduced by NAD(P)H and to generate superoxide radicals. The growth response of the various cell types was measured by colony-forming ability as well as by tritiated thymidine incorporation using autoradiography. At low paraquat concentrations (25 microM), primary SHE cells and two sup+ clones showed up to a 40% enhancement in colony formation, while two sup- clones showed no increase. Toxicity was observed at high doses, starting at approximately 100 microM paraquat. Since oxygen radicals are also mutagenic, primary SHE cells were examined for chromosomal aberrations. Chromatid gaps and breaks were induced at all concentrations of paraquat used. Thus, superoxide not only causes cellular toxicity at high doses but at low doses enhances cell growth of certain cells (primary SHE cells and sup+ cells) but not others (sup- cells). Therefore, differing responses of cells at different stages of neoplastic progression must be considered in understanding oxygen radical effects in growth control and carcinogenesis.
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Sciences, NIH, Research Triangle Park, North Carolina 27709.
T M
TM
Nicotera
C
C
Privalle
T C
TC
Wang
M
M
Oshimura
J C
JC
Barrett
D000818:Animals; D002374:Catalase / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000187:drug effects; D005609:Free Radicals; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D008647:Mesocricetus; D010269:Paraquat / Q000633:toxicity*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000633:toxicity*
D005609:Free Radicals; D013481:Superoxides; D002374:Catalase; D013482:Superoxide Dismutase; D010269:Paraquat