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First published on February 26, 2007; DOI: 10.1124/mol.106.032284

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Received for publication November 1, 2006.
Revised February 21, 2007.
Accepted for publication February 21, 2007.

Antiproliferative Mechanisms of a Transcription Factor Decoy Targeting STAT3: the Role of STAT1

Vivian W. Y. Lui 1, Amanda L. Boehm 2, Priya Koppikar 3, Rebecca J. Leeman 3, Daniel Johnson 4, Michelene J. Ogagan 3, Erin E. Childs 3, Maria Freilino 3, Jennifer R. Grandis 5*

1 The Chinese University of Hong Kong 2 University of Pittsburgh, Departments of Pathology and Otolaryngology 3 University of Pittsburgh, Department of Otolaryngology 4 University of Pittsburgh, Departments of Pharmacology & Medicine 5 University of Pittsburgh, Departments of Otolaryngology & Pharmacology

* Address correspondence to: E-mail: jgrandis{at}pitt.edu

Abstract

We previously developed a transcription factor decoy targeting STAT3 and reported antitumor activity in both in vitro and in vivo models of squamous cell carcinoma of the head and neck (SCCHN). Based on the known existence of STAT1-STAT3 heterodimers, the high sequence homology between STAT1 and STAT3, as well as expression of both STAT1 and STAT3 in SCCHN, we examined whether the STAT3 decoy interferes with STAT1 signaling. SCCHN cell lines with different STAT1 expression levels (but similar STAT3 levels) were used. Both cell lines were sensitive to the growth inhibitory effects of the STAT3 decoy compared to a mutant control decoy. Intact STAT1 signaling was demonstrated by interferon-gamma (IFN-{gamma}) -mediated induction of STAT1 phosphorylation (Tyr701) and interferon-regulatory factor-1 (IRF-1) expression. Treatment with the STAT3 decoy (but not a mutant control decoy) resulted in inhibition of IRF-1 protein expression in both cell lines, indicating specific inhibition of STAT1 signaling by the STAT3 decoy. As STAT1 is a potential tumor suppressor, we also investigated whether the therapeutic efficacy of the STAT3 decoy was mitigated by STAT1 signaling. In both PCI-15B and UM-22B cells, STAT1 siRNA treatment resulted in decreased STAT1 expression, without altering the antitumor activity of the STAT3 decoy. Similarly, the antitumor effects of the STAT3 decoy were not altered by STAT1 activation upon IFN-{gamma} treatment. These results suggest that the therapeutic mechanisms of STAT3 blockade using a transcription factor decoy are independent of STAT1 activation.


Key words: Jak/Stats, Regulation of gene expression, Transcription targets




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