Abstract
The role of intracellular oxidative stress in the mechanism of action of phosphotyrosine phosphatase (PTP) inhibitors was studied using three vanadium-based compounds. Sodium orthovanadate (Na3VO4), sodium oxodiperoxo(1,10-phenanthroline)vanadate(V) (pV(phen), and bis(maltolato)-oxovanadium(IV) (BMOV) differentially induced oxidative stress in lymphocytes. Treatment with pV(phen), which caused intracellular oxidation, induced strong protein tyrosine phosphorylation compared with Na3VO4 and BMOV. Syk family kinases and the mitogen-activated protein kinase erk2 were rapidly activated by pV(phen) but not by BMOV or Na3VO4. In contrast, both BMOV and pV(phen) strongly activated NF-kappaB. The antioxidant pyrrolidine dithiocarbamate (PDTC) greatly diminished the intracellular oxidation and protein phosphotyrosine accumulation induced by pV(phen). Pretreatment of cells with PDTC reduced and delayed the activation of Syk kinases and erk2. However, NF-kappaB activation by pV(phen) was markedly enhanced in lymphocytes pretreated with PDTC, and another antioxidant, N-acetylcysteine, did not prevent the activation of NF-kappaB by BMOV. These results indicate a role for oxidative stress in the biological effects of some PTP inhibitors, whereas NF-kappaB activation by PTP inhibitors is mediated by mechanisms independent of intracellular redox status.
Highlights
The role of intracellular oxidative stress in the mechanism of action of phosphotyrosine phosphatase (PTP) inhibitors was studied using three vanadiumbased compounds
These results indicate a role for oxidative stress in the biological effects of some PTP inhibitors, whereas NF-B activation by PTP inhibitors is mediated by mechanisms independent of intracellular redox status
Treatment with BMOV resulted in slightly increased phosphotyrosine levels in Ramos cells; the induction was substantially less than previously observed with longer treatment times [15]
Summary
The MAPK erk was activated by pV(phen) but not by BMOV or Na3VO4 in both cell lines. Both BMOV and pV(phen) strongly activated the transcription factor NF-B. Pretreatment with antioxidants prevented development of intracellular oxidation and greatly diminished both the pV(phen)-induced accumulation of protein tyrosine phosphorylation and the activation of Syk, ZAP-70, and erk following pV(phen) treatment. Antioxidant treatment did not prevent the activation of NF-B by BMOV or pV(phen). These results indicate that for many of the effects of pV(phen), the generation of oxidative stress is necessary. We bring together results from vanadium compounds that differ in their ability to induce intracellular oxidation, along with effects of antioxidants on PTP inhibitor action, to provide novel evidence for the redoxindependent activation of NF-B triggered by PTP inhibition
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