In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer
Sichuan Xi1, William E Gooding, Jennifer Rubin Grandis
1Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Abstract:
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.
Insights
Blocking Signal Transducers and Activators of Transcription 3 (STAT3) with a decoy approach significantly reduced tumor growth and STAT3 activation in head and neck cancers. This method also enhanced the effectiveness of chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Solid tumor treatment is hindered by a lack of understanding of cancer growth pathways.
- Signal transducers and activators of transcription (STAT) proteins, particularly STAT3, are implicated in cancer development and progression.
- Previous studies show blocking STAT3 can reduce cancer cell proliferation and induce apoptosis.
Purpose of the Study:
- To investigate if blocking STAT3 activation using a transcription factor decoy approach can inhibit tumor growth and STAT3 target gene expression in vivo.
- To evaluate the efficacy of the STAT3 decoy alone and in combination with cisplatin in a head and neck squamous cell carcinoma (SCCHN) model.
Main Methods:
- A xenograft model of SCCHN was used to test the STAT3 decoy.
- Daily administration of 25 microg of the STAT3 decoy or a mutant control decoy.
- Assessed tumor volume, STAT3 activation, expression of STAT3 target genes (VEGF, Bcl-xL, cyclin D1), apoptosis, and proliferation.
- Evaluated the combination of STAT3 decoy and cisplatin both in vitro and in vivo.
Main Results:
- Daily STAT3 decoy treatment significantly decreased tumor volumes compared to the control decoy.
- STAT3 activation was abrogated, and expression of STAT3 target genes (VEGF, Bcl-xL, cyclin D1) was reduced.
- STAT3 decoy treatment induced apoptosis and decreased proliferation.
- Combining the STAT3 decoy with cisplatin further augmented these anti-cancer effects.
Conclusions:
- A transcription factor decoy approach effectively blocks STAT3 activation and inhibits tumor growth in SCCHN.
- This strategy holds promise for targeting STAT3 in cancers with elevated STAT3 activity.
- The STAT3 decoy can enhance the efficacy of chemotherapy, suggesting potential for combination therapies.
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