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 Kenneth Cowell, Heinz Baumann

Research output: Contribution to journalArticle

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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

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STAT Transcription Factors
Protein-Tyrosine Kinases
Phosphorylation
Acute Myeloid Leukemia
Receptor, Fibroblast Growth Factor, Type 1
Janus Kinases
Myeloid Cells
arsenic trioxide
STAT3 Transcription Factor
Protein Kinases
Cell Death
Research Design
Down-Regulation
Clinical Trials

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Arsenic trioxide affects signal transducer and activator of transcription proteins through alteration of protein tyrosine kinase phosphorylation. / Wetzler, Meir; Brady, Michael T.; Tracy, Erin; Li, Zhang Rong; Donohue, Kathleen A.; O'Loughlin, Kieran L.; Cheng, Yijun; Mortazavi, Amir; McDonald, Amy A.; Kunapuli, Padmaja; Wallace, Paul K.; Baer, Maria R.; Cowell, John Kenneth; Baumann, Heinz.

In: Clinical Cancer Research, Vol. 12, No. 22, 15.11.2006, p. 6817-6825.

Research output: Contribution to journalArticle

Wetzler, M, Brady, MT, Tracy, E, Li, ZR, Donohue, KA, O'Loughlin, KL, Cheng, Y, Mortazavi, A, McDonald, AA, Kunapuli, P, Wallace, PK, Baer, MR, Cowell, JK & Baumann, H 2006, 'Arsenic trioxide affects signal transducer and activator of transcription proteins through alteration of protein tyrosine kinase phosphorylation', Clinical Cancer Research, vol. 12, no. 22, pp. 6817-6825. https://doi.org/10.1158/1078-0432.CCR-06-1354
Wetzler, Meir ; Brady, Michael T. ; Tracy, Erin ; Li, Zhang Rong ; Donohue, Kathleen A. ; O'Loughlin, Kieran L. ; Cheng, Yijun ; Mortazavi, Amir ; McDonald, Amy A. ; Kunapuli, Padmaja ; Wallace, Paul K. ; Baer, Maria R. ; Cowell, John Kenneth ; Baumann, Heinz. / Arsenic trioxide affects signal transducer and activator of transcription proteins through alteration of protein tyrosine kinase phosphorylation. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 22. pp. 6817-6825.
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AU - O'Loughlin, Kieran L.

AU - Cheng, Yijun

AU - Mortazavi, Amir

AU - McDonald, Amy A.

AU - Kunapuli, Padmaja

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