title: Tolfenamic acid downregulates β-catenin in colon cancer.
abstract: Tolfenamic acid is one of the fenamic acid-derived non-steroid anti-inflammatory drugs (NSAIDs) and has been shown to exhibit anti-cancer activities in several types of cancer. Both mutations and aberrant expression of β-catenin are highly associated with progression of cancer. Therefore, β-catenin is considered to be a promising molecular target for cancer prevention and treatment. The current study investigates the role of tolfenamic acid on β-catenin expression in colon cancer. Treatment with tolfenamic acid led to inhibition of cell growth and down-regulation of β-catenin expression in a dose- and time-dependent manner in human colon cancer cell lines. Reduction of β-catenin upon tolfenamic acid treatment was associated with ubiquitin-mediated proteasomal degradation, without affecting mRNA level and promoter activity of β-catenin. In addition, treatment with tolfenamic acid downregulated Smad2 and Smad3 expression, while overexpression of Smad2, but not Smad3, blocked tolfenamic acid-induced suppression of β-catenin expression. Tolfenamic acid also decreased expression of β-catenin target genes, including vascular endothelial growth factor (VEGF). Compared to adjacent normal tissue, intestinal tumor tissues of Apc(Min/+) mice exhibited increased expression of β-catenin, Smad2, Smad3, and VEGF, which were down-regulated with tolfenamic acid treatment at a dose of 50mg/kg body weight. In conclusion, our findings suggest that tolfenamic acid inhibits growth of colon cancer cells through downregulation of Smad2 and, subsequently, facilitating ubiquitin-proteasome-mediated β-catenin degradation in colon cancer.
authors.affiliation: Department of Nutrition and Food Science, College of Agriculture and Natural Resources, University of Maryland, College Park, MD 20742, USA.
authors.forename: Taekyu
authors.initials: T
authors.lastname: Ha
authors.affiliation: Department of Nutrition and Food Science, College of Agriculture and Natural Resources, University of Maryland, College Park, MD 20742, USA.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Lou
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Baek
authors.affiliation: Department of Nutrition and Food Science, College of Agriculture and Natural Resources, University of Maryland, College Park, MD 20742, USA. Electronic address: slee2000@umd.edu.
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid; D046988:Proteasome Endopeptidase Complex
keywords: Colon cancer; Smad2; Tolfenamic acid; β-catenin