Toxicological Sciences, Vol 50, 72-81, Copyright © 1999 by Society of Toxicology
KJ Trouba, JG Glanzer and RL Vorce
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.
ARTICLES
Wild-type and Ras-transformed fibroblasts display differential mitogenic responses to transient sodium arsenite exposure
Department of Pharmacology and Center for Environmental Toxicology, University of Nebraska Medical Center, Omaha 68198-6260, USA.
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