Antiproliferative Mechanisms of a Transcription Factor Decoy Targeting Signal Transducer and Activator of Transcription (STAT) 3: The Role of STAT1

Abstract

We previously developed a transcription factor decoy targeting signal transducer and activator of transcription 3 (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 with a mutant control decoy. Intact STAT1 signaling was demonstrated by interferon-␥ (IFN-␥)-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. Because STAT1 is a potential tumor suppressor, we also investigated whether STAT1 signaling mitigated the therapeutic efficacy of the STAT3 decoy. 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. Likewise, the antitumor effects of the STAT3 decoy were not altered by STAT1 activation upon IFN-␥ treatment. These results suggest that the therapeutic mechanisms of STAT3 blockade using a transcription factor decoy are independent of STAT1 activation.Signal transducer and activator of transcription 3 (STAT3) has emerged as a potential molecular target for cancer therapy. STAT3 is constitutively activated and overexpressed in a variety of human malignancies, including breast, lung, prostate, brain, leukemia, multiple myeloma, and squamous cell carcinoma of the head and neck (SCCHN) (Grandis et al., 1998;Turkson and Jove, 2000). The expression levels of activated or tyrosine-phosphorylated STAT3 have been reported to correlate with decreased survival in several cancers, including oral tongue carcinoma (Masuda et al., 2002). Molecular targeting of STAT3 using a variety of strategies in preclinical models of human cancer has been shown to inhibit tumor growth (Turkson and Jove, 2000). We previously developed a transcription factor decoy based on the STAT3 DNA binding element and demonstrated that this decoy interferes with STAT3 signaling and decreases SCCHN tumor growth in vitro and in vivo (Leong et al., 2003;Xi et al., 2005).Transcription factor decoys are double-stranded DNA oligonucleotides that resemble the transcription factor-binding site in the promoters of target genes. Transcription factor decoys presumably bind transcription factors and sequester the targeted transcription factor, rendering it unavailable for transcription of downstream target genes. The sequence of the STAT3 decoy was derived from the serum-inducible element of the human c-fos...

LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model

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Cucurbitacin I inhibits cell migration and invasion and enhances chemosensitivity in colon cancer

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