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PNAS 100 (7): 4138-4143

Copyright © 2003 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth

Paul L. Leong*,{dagger}, Genevieve A. Andrews*,{dagger}, Daniel E. Johnson{ddagger},§, 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, {ddagger}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

Received for publication August 7, 2002.

Abstract: 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.

{dagger} P.L.L. and G.A.A. contributed equally to this work.

** To whom correspondence should be addressed. E-mail: jgrandis{at}pitt.edu.

Edited by James E. Darnell, Jr., The Rockefeller University, New York, NY, and approved December 2, 2002

This paper was submitted directly (Track II) to the PNAS office.

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