Arsenic trioxide affects signal transducer and activator of transcription proteins through alteration of protein tyrosine kinase phosphorylation

Meir Wetzler, Michael T. Brady, Erin Tracy, Zhang Rong Li, Kathleen A. Donohue, Kieran L. O'Loughlin, Yijun Cheng, Amir Mortazavi, Amy A. McDonald, Padmaja Kunapuli, Paul K. Wallace, Maria R. Baer, John K. Cowell, Heinz Baumann

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Purpose: Arsenic trioxide decreases proliferation of acute myeloid leukemia (AML) cells, but its precise mechanism of action is unknown. Experimental Design: We studied the effect of arsenic trioxide on patient samples and the AML cell line HEL, which, like leukemic blasts from 50% of AML cases, has constitutively activated signal transducer and activator of transcription (STAT) proteins. Results: Arsenic trioxide induced mitotic arrest starting at 24 hours and significant cell death at 48 hours. These events were preceded by an arsenic trioxide dose-dependent down-regulation of activated STAT proteins starting at 6 hours. We hypothesized that arsenic trioxide inhibits protein tyrosine kinases (PTK), which, among others, phosphorylate and activate STATs. We therefore studied arsenic trioxide effects on Janus kinases and on three oncogenic PTKs that are known to activate STATs [FLT3, ZNP198/fibroblast growth factor receptor 1 (FGFR1), and BCR/ABL]. Arsenic trioxide reduced STAT3 activation by Janus kinases, altered phosphorylation and electrophoretic mobility of ZNF198/fibroblast growth factor receptor 1, reduced kinase protein level, and decreased STAT3 protein phosphorylation. Arsenic trioxide also reduced the phosphorylation of BCR/ABL and FLT3 with corresponding decreased STAT5 phosphorylation. Conclusions: These results suggest a selective activity of arsenic trioxide on PTKs and will assist in developing clinical trials in AML.

Original languageEnglish (US)
Pages (from-to)6817-6825
Number of pages9
JournalClinical Cancer Research
Volume12
Issue number22
DOIs
StatePublished - Nov 15 2006
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wetzler, M., Brady, M. T., Tracy, E., Li, Z. R., Donohue, K. A., O'Loughlin, K. L., Cheng, Y., Mortazavi, A., McDonald, A. A., Kunapuli, P., Wallace, P. K., Baer, M. R., Cowell, J. K., & Baumann, H. (2006). Arsenic trioxide affects signal transducer and activator of transcription proteins through alteration of protein tyrosine kinase phosphorylation. Clinical Cancer Research, 12(22), 6817-6825. https://doi.org/10.1158/1078-0432.CCR-06-1354