Wild-type and Ras-transformed fibroblasts display differential mitogenic responses to transient sodium arsenite exposure.
Arsenic is a human carcinogen whose mechanism of action remains undefined. Based on the hypothesis that arsenic sensitizes cells to mitogenic stimulation by affecting the receptor tyrosine kinase (RTK) signal transduction pathway, these studies first examined the response of fibroblasts to specific mitogens using a defined media system. In both rodent and human fibroblasts, DNA synthesis was found to be stimulated in cells exposed to a transient, sub-lethal concentration of sodium arsenite followed by stimulation with known RTK pathway activators. This effect is observed for up to 32 h after removal of arsenic, suggesting that the RTK pathway is affected in a sustained manner. In contrast, transient arsenic exposure of ras-transformed cells results in decreased mitogen-stimulated DNA synthesis. Flow cytometry indicates that arsenic increases the percentage of wild-type cells in the S-phase of the cell cycle; conversely, the percentage of ras-transformed cells in S-phase is decreased by arsenic. No evidence of arsenic-induced cytotoxicity was detected using the neutral red assay, ensuring that decreased DNA synthesis in ras-transformed cells is not due to cell death. Taken together, the results of experiments presented herein indicate that arsenic produces sustained alterations in the growth characteristics of rodent and human fibroblasts. It is postulated that the proliferation-enhancing effect of arsenic on wild-type cells contributes to its ability to cause cancer.
Trouba
K J
KJ
Department of Pharmacology and Center for Environmental Toxicology, University of Nebraska Medical Center, Omaha 68198-6260, USA.
Glanzer
J G
JG
Vorce
R L
RL
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002461:Cell Line, Transformed; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects*; D005434:Flow Cytometry; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D017670:Sodium Compounds / Q000633:toxicity*; D013997:Time Factors
D018053:Arsenites; D002273:Carcinogens; D008934:Mitogens; D017670:Sodium Compounds; C017947:sodium arsenite; D004247:DNA; D011505:Protein-Tyrosine Kinases