In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy.
The development of more effective prevention and treatment strategies for solid tumors is limited by an incomplete understanding of the critical growth pathways that are activated in carcinogenesis. Signal transducers and activators of transcription (STAT) proteins have been linked to transformation and tumor progression. Several approaches have been used to block STAT3 in cancer cells resulting in reduced proliferation and apoptosis. We tested the hypothesis that blocking STAT3 activation using a transcription factor decoy approach would decrease tumor growth and STAT3 target gene expression in vivo. In a xenograft model of squamous cell carcinoma of the head and neck (SCCHN), daily administration of the STAT3 decoy (25 microg) resulted in decreased tumor volumes, abrogation of STAT3 activation, and decreased expression of STAT3 target genes (VEGF, Bcl-xL, and cyclin D1) compared to treatment with a mutant control decoy. Blockade of STAT3 with the STAT3 decoy also induced apoptosis and decreased proliferation, an effect that was augmented when the STAT3 decoy was combined with cisplatin, both in vitro and in vivo. These results suggest that a transcription factor decoy approach may be used to target STAT3 in cancers that demonstrate increased STAT3 activation including SCCHN.
Xi
Sichuan
S
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Gooding
William E
WE
Grandis
Jennifer Rubin
JR
D000209:Acute-Phase Proteins; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002945:Cisplatin / Q000494:pharmacology; D019938:Cyclin D1 / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology; D015536:Down-Regulation; D015316:Genetic Therapy / Q000379:methods; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology; D014157:Transcription Factors; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D051020:bcl-X Protein
D000209:Acute-Phase Proteins; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; D019938:Cyclin D1; D002945:Cisplatin