Chronic exposures to inorganic
arsenic (iAs) have been linked to increased incidences of various
cancers, including
cancer of the urinary bladder. Mechanisms by which iAs promotes
cancer may include stimulation of
activator protein-1 (AP-1)
DNA binding through increased expression and/or phosphorylation of the
AP-1 constituents. However, the role of methylated metabolites of iAs in
AP-1 activation has not been thoroughly examined. In this study, we show that short-time exposures to 0.1-5 microM
arsenite (iAsIII) or the methylated trivalent
arsenicals methylarsine oxide (MAsIIIO), or iododimethylarsine (DMAsIIII) induce phosphorylation of c-Jun and increase
AP-1 DNA binding activity in human bladder epithelial cells. DMAsIIII and especially MAsIIIO are considerably more potent than iAsIII as inducers of c-Jun phosphorylation and
AP-1 activation. Phosphorylated c-Jun, JunB, JunD, and Fra-1, but not c-Fos, FosB, or ATF-2, are detected in the AP-1-DNA binding complex in cells exposed to trivalent
arsenicals. In cells transiently transfected with an AP-1-dependent promoter-reporter construct, MAsIIIO was more potent than iAsIII in inducing the AP-1-dependent gene transcription. Exposures to trivalent
arsenicals induce phosphorylation of
extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal
kinases or p38
kinases. These results indicate that an ERK-dependent signal transduction pathway is at least partially responsible for c-Jun phosphorylation and
AP-1 activation in UROtsa cells exposed to inorganic or methylated trivalent
arsenicals.