APE1/Ref-1 Regulates STAT3 Transcriptional Activity and APE1/Ref-1–STAT3 Dual-Targeting Effectively Inhibits Pancreatic Cancer Cell Survival
| Autor: | Mark R. Kelley, April Reed, Meihua Luo, Yanlin Jiang, Safi Shahda, Angelo A. Cardoso, Melissa L. Fishel, Anirban Maitra, Ying He |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Redox signaling
Transcription Genetic Cancer Treatment lcsh:Medicine Apoptosis Signal transduction 0302 clinical medicine Molecular cell biology Basic Cancer Research Transcriptional regulation Benzoquinones DNA-(Apurinic or Apyrimidinic Site) Lyase Molecular Targeted Therapy RNA Small Interfering STAT3 lcsh:Science Cellular Stress Responses Regulation of gene expression 0303 health sciences Multidisciplinary Cell Death Caspase 3 Benzenesulfonates 3. Good health Cyclic S-Oxides Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis Gene Knockdown Techniques Medicine Oxidation-Reduction Intracellular Research Article STAT3 Transcription Factor DNA transcription Signaling in cellular processes Biology Adenocarcinoma 03 medical and health sciences Pancreatic Cancer Cell Line Tumor Gastrointestinal Tumors Humans Transcription factor 030304 developmental biology Cell Proliferation STAT signaling family Cell growth lcsh:R Cancers and Neoplasms Blockade Pancreatic Neoplasms Aminosalicylic Acids biology.protein Cancer research lcsh:Q Gene expression Propionates |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 10, p e47462 (2012) |
| ISSN: | 1932-6203 |
| Popis: | Pancreatic cancer is a largely incurable disease, and increasing evidence supports strategies targeting multiple molecular mediators of critical functions of pancreatic ductal adenocarcinoma cells. Intracellular redox state modulates the activity of various signal transduction pathways and biological processes, including cell survival, drug resistance and responsiveness to microenvironmental factors. Recently, it has been shown that the transcription factor STAT3 is under redox control, but the mechanisms involved in its regulation are unknown. Here, we demonstrate for the first time that STAT3 DNA binding and transcriptional activity is directly regulated by the redox function of the APE1/Ref-1 endonuclease, using overexpression and redox-specific mutational strategies, and gene knockdown. Also, pharmacological blockade of APE1/Ref-1 by the redox-selective inhibitor E3330 abrogates STAT3 DNA binding. Since APE1/Ref-1 also exerts redox control on other cancer-associated transcription factors, we assessed the impact of dual-targeting of STAT3 signaling and APE1/Ref-1 redox on pancreatic cancer cell functions. We observed that disruption of APE1/Ref-1 redox activity synergizes with STAT3 blockade to potently inhibit the proliferation and viability of human PDAC cells. Mechanistically, we show that STAT3–APE1/Ref-1 dual targeting promotes marked tumor cell apoptosis, with engagement of caspase-3 signaling, which are significantly increased in comparison to the effects triggered by single target blockade. Also, we show that STAT3–APE1/Ref-1 dual blockade results in significant inhibition of tumor cell migration. Overall, this work demonstrates that the transcriptional activity of STAT3 is directly regulated by the redox function of APE1/Ref-1, and that concurrent blockade of STAT3 and APE1/Ref-1 redox synergize effectively inhibit critical PDAC cell functions. |
| Databáze: | OpenAIRE |
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