[STAT3 inhibition, head & neck]
>>Published online before print March 14, 2003
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0534764100
Medical Sciences
Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth
Paul L. Leong *, Genevieve A. Andrews *, Daniel E. Johnson , Kevin F. Dyer *, Sichuan Xi *, Jeffrey C. Mai ¶, Paul D. Robbins ¶, Seshu Gadiparthi *, Nancy A. Burke ||, Simon F. Watkins ||, and Jennifer Rubin Grandis ***
Departments of *Otolaryngology, Medicine, Pharmacology, ¶Molecular Genetics and Biochemistry, and ||Cell Biology and Physiology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15260
Edited by James E. Darnell, Jr., The Rockefeller University, New York, NY, and approved December 2, 2002 (received for review August 7, 2002)
The transcription factor signal transducer and activator of transcription 3 (Stat3) is constitutively activated in a variety of cancers including squamous cell carcinoma of the head and neck (SCCHN). Previous investigations have demonstrated that activated Stat3 contributes to a loss of growth control and transformation. To investigate the therapeutic potential of blocking Stat3 in cancer cells, we developed a transcription factor decoy to selectively abrogate activated Stat3. The Stat3 decoy was composed of a 15-mer double-stranded oligonucleotide, which corresponded closely to the Stat3 response element within the c-fos promoter. The Stat3 decoy bound specifically to activated Stat3 and blocked binding of Stat3 to a radiolabeled Stat3 binding element. By contrast, a mutated version of the decoy that differed by only a single base pair did not bind the activated Stat3 protein. Treatment of head and neck cancer cells with the Stat3 decoy inhibited proliferation and Stat3-mediated gene expression, but did not decrease the proliferation of normal oral keratinocytes. Thus, disruption of activated Stat3 by using a transcription factor decoy approach may serve as a novel therapeutic strategy for cancers characterized by constitutive Stat3 activation.<<
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