Impairment of antioxidant defenses as a contributor to arsenite-induced cell transformation.
Arsenite (As) causes transformation of human osteogenic sarcoma cells (HOS) when applied continuously at low doses (0.1-0.5 μM) during 8-weeks of exposure. However, the mechanisms by which As transforms human cells are not known. We investigated whether alterations occurred in gene expression and protein levels of antioxidant defense proteins, such as superoxide dismutase 1 (SOD1) and ferritin. In comparison to control HOS cells, 0.1 μM As induced greater cell proliferation and decreased anti-oxidant defenses. The tumor suppressor protein p53 was also decreased at both mRNA and protein levels. Further, pig3 (p53-induced-gene 3), a homolog of NQO1 (NADPH quinone oxidoreductase 1), was also down-regulated after 8 weeks of As challenge. The treatment of HOS cells with dicumarol, a NQO1 inhibitor, caused a dose-dependent decline in p53 protein levels, proving the effect of an antioxidant enzyme on p53 expression and, potentially, down-stream processes. Caffeic acid phenethyl ester, an antioxidant, prevented the As-induced decreases in SOD1, p53, and ferritin mRNA and protein levels. SOD1, p53 and ferritin levels were inversely related to As-induced cell proliferation. Cumulatively, these results strongly suggest that impairment in antioxidant defenses contributes to As-induced human cell transformation and that the p53 pathway is involved in the process.
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10016, USA. wuj04@nyumc.org
Jing
J
Wu
Anna
A
Sowinska
Xi
X
Huang
Catherine B
CB
Klein
Edward
E
Pelle
Krystyna
K
Frenkel
D000975:Antioxidants / Q000378:metabolism*; D018053:Arsenites / Q000633:toxicity*; D002109:Caffeic Acids / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D001728:Dicumarol / Q000494:pharmacology; D004785:Environmental Pollutants / Q000633:toxicity; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D018053:Arsenites; D002109:Caffeic Acids; D004785:Environmental Pollutants; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C000606290:SOD1 protein, human; C495901:TP53 protein, human; C411296:TP53I3 protein, human; D016159:Tumor Suppressor Protein p53; D001728:Dicumarol; D005293:Ferritins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol; C015001:arsenite