Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth.
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.
Leong
Paul L
PL
Department of Otolaryngology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15260, USA.
Andrews
Genevieve A
GA
Johnson
Daniel E
DE
Dyer
Kevin F
KF
Xi
Sichuan
S
Mai
Jeffrey C
JC
Robbins
Paul D
PD
Gadiparthi
Seshu
S
Burke
Nancy A
NA
Watkins
Simon F
SF
Grandis
Jennifer Rubin
JR
D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D004268:DNA-Binding Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D051020:bcl-X Protein; D008156:Luciferases