Squamous cell carcinoma of the head and neck (SCCHN) is the 5th most common cancer worldwide. Signal transducer and activator of transcription 3 (STAT3) is overexpressed in SCCHN and associated with decreased survival. A transcription factor decoy was designed to bind to the DNA binding domain of STAT3, abrogating expression of downstream target genes. The antitumor mechanisms of transcription factor decoys, including the STAT3 decoy, are incompletely understood. STAT3 forms heterodimers with STAT1 suggesting that the STAT3 decoy may interact with STAT1. We determined that the STAT1 pathway was functional in SCCHN cell lines. The STAT3 decoy inhibited STAT1-mediated expression of the target gene, IRF-1. Stimulation of the STAT1 pathway with IFN-× did not mitigate STAT3 decoy-mediated growth inhibition. STAT3 decoy-mediated inhibition of STAT1 signaling did not abrogate its antitumor effects in vitro. Studies using STAT3 knockout cells indicated that STAT3 is necessary for decoy-mediated growth inhibition. The STAT3 decoy was then studied in combination with an EGFR inhibitor and/or a Bcl-XL inhibitor as a therapeutic strategy for SCCHN. Targeting this pathway at several levels¡Xthe upstream receptor (EGFR), the intracellular transcription factor (STAT3), and the downstream target gene (Bcl-XL)¡Xhas not been previously investigated. Combined targeting of EGFR and STAT3 using erlotinib and the STAT3 decoy enhanced growth inhibition of SCCHN cells in vitro. The STAT3 decoy in combination with gossypol, a Bcl-XL inhibitor, resulted in enhanced growth inhibition. The triple combination of all 3 agents enhanced growth inhibition in vitro. These results indicate that targeting the EGFR-STAT3-Bcl-XL pathway at three distinct levels may be a promising treatment strategy for SCCHN.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04032007-154335 |
| Date | 18 April 2007 |
| Creators | Boehm, Amanda L. |
| Contributors | Reza Zarnegar, Marie DeFrances, Daniel E. Johnson, Jennifer R. Grandis, Alan Wells |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04032007-154335/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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