Carcinogenesis Advance Access originally published online on April 30, 2009
Carcinogenesis 2009 30(7):1193-1201; doi:10.1093/carcin/bgp092
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Tolfenamic acid inhibits esophageal cancer through repression of specificity proteins and c-Met
1 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA
2 Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030-3303, USA
3 Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, FL 32806, USA
4 Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843-4458, USA
5 Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
* To whom correspondence should be addressed. Tel: +1 979 845 5988; Fax: +1 979 862 4929; Email: ssafe{at}cvm.tamu.edu
The non-steroidal anti-inflammatory drug tolfenamic acid (TA) inhibits proliferation of SEG-1 and BIC-1 esophageal cancer cells with half-maximal growth inhibitory concentration values of 36 and 48 µM, respectively. TA also increased Annexin V staining in both cell lines, indicative of proapoptotic activity. Treatment of SEG-1 and BIC-1 cells with TA for up to 72 h decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and this was accompanied by decreased expression of the well-characterized Sp-regulated genes cyclin D1, vascular endothelial growth factor and survivin. TA also decreased hepatocyte growth factor receptor, (c-Met), a receptor tyrosine kinase that is overexpressed in esophageal cancer cells and tumors and is an important drug target. Knockdown of Sp1, Sp3 and Sp4 by RNA interference in SEG-1 and BIC-1 cells also decreased c-Met expression, demonstrating that c-Met is an Sp-regulated gene in esophageal cancer cells. Sp1 was overexpressed in esophageal cancer cells and tumors and increased Sp1 staining was observed in esophageal tumors from patients. TA (20 mg/kg/day) also decreased tumor growth and weight in athymic nude mice bearing SEG-1 cells as xenografts and this was accompanied by increased apoptosis and decreased Sp1 and c-Met staining in tumors from treated mice. Thus, TA-dependent downregulation of Sp transcription factors and c-Met defines a novel chemotherapeutic approach for treatment of esophageal cancer.
Abbreviations: c-Met, hepatocyte growth factor receptor; DMEM, Dulbecco's modified Eagle's medium; EC, esophageal cancer; FBS, fetal bovine serum; β-gal, β-galactosidase; PBS, phosphate-buffered saline; siRNA, small inhibitory RNA; Sp, specificity protein; TA, tolfenamic acid; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; VEGF, vascular endothelial growth factor
These authors contributed equally to this work. Received February 19, 2009; revised April 6, 2009; accepted April 9, 2009.