Tolfenamic acid downregulates β-catenin in colon cancer
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...
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| Veröffentlicht in: | International immunopharmacology 2016-06, Vol.35, p.287-293 |
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| creator | Ha, Taekyu Lou, Zhiyuan Baek, Seung Joon Lee, Seong-Ho |
| description | 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 ApcMin/+ 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.
•Anticancer mechanism of tolfenamic acid is proposed.•The mechanism relies on activating proteasomal degradation of β-catenin.•Smad2 mediates tolfenamic acid-induced downregulation of β-catenin. |
| doi_str_mv | 10.1016/j.intimp.2016.04.008 |
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•Anticancer mechanism of tolfenamic acid is proposed.•The mechanism relies on activating proteasomal degradation of β-catenin.•Smad2 mediates tolfenamic acid-induced downregulation of β-catenin.</description><identifier>ISSN: 1567-5769</identifier><identifier>EISSN: 1878-1705</identifier><identifier>DOI: 10.1016/j.intimp.2016.04.008</identifier><identifier>PMID: 27089389</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Animals ; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use ; beta Catenin - genetics ; beta Catenin - metabolism ; Cell Line, Tumor ; Colon cancer ; Colonic Neoplasms - drug therapy ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Mice, Mutant Strains ; ortho-Aminobenzoates - therapeutic use ; Proteasome Endopeptidase Complex - metabolism ; Smad2 ; Smad2 Protein - genetics ; Smad2 Protein - metabolism ; Smad3 Protein - genetics ; Smad3 Protein - metabolism ; Tolfenamic acid ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism ; β-catenin</subject><ispartof>International immunopharmacology, 2016-06, Vol.35, p.287-293</ispartof><rights>2016 Elsevier B.V.</rights><rights>Copyright © 2016 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c395t-27c4de9ed5658e64336ef6bc4b0b768f09957cee44c604e58f3a3174a176a9bc3</citedby><cites>FETCH-LOGICAL-c395t-27c4de9ed5658e64336ef6bc4b0b768f09957cee44c604e58f3a3174a176a9bc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.intimp.2016.04.008$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27089389$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ha, Taekyu</creatorcontrib><creatorcontrib>Lou, Zhiyuan</creatorcontrib><creatorcontrib>Baek, Seung Joon</creatorcontrib><creatorcontrib>Lee, Seong-Ho</creatorcontrib><title>Tolfenamic acid downregulates β-catenin in colon cancer</title><title>International immunopharmacology</title><addtitle>Int Immunopharmacol</addtitle><description>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 ApcMin/+ 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.
•Anticancer mechanism of tolfenamic acid is proposed.•The mechanism relies on activating proteasomal degradation of β-catenin.•Smad2 mediates tolfenamic acid-induced downregulation of β-catenin.</description><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - therapeutic use</subject><subject>beta Catenin - genetics</subject><subject>beta Catenin - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Down-Regulation</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>ortho-Aminobenzoates - therapeutic use</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Smad2</subject><subject>Smad2 Protein - genetics</subject><subject>Smad2 Protein - metabolism</subject><subject>Smad3 Protein - genetics</subject><subject>Smad3 Protein - metabolism</subject><subject>Tolfenamic acid</subject><subject>Vascular Endothelial Growth Factor A - genetics</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><subject>β-catenin</subject><issn>1567-5769</issn><issn>1878-1705</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkM1KxDAQgIMo7rr6BiI9emlN2vxeBFn8gwUv6zmk6VSy9GdNWsXX8kF8JrN09ShCSCbDNzPMh9A5wRnBhF9tMtcNrt1mefxlmGYYywM0J1LIlAjMDmPMuEiZ4GqGTkLYYBzzlByjWS6wVIVUcyTXfVNDZ1pnE2NdlVT9e-fhZWzMACH5-kxtDDrXJfHYvunjbToL_hQd1aYJcLZ_F-j57na9fEhXT_ePy5tVagvFhjQXllagoGKcSeC0KDjUvLS0xKXgssZKMWEBKLUcU2CyLkxBBDVEcKNKWyzQ5dR36_vXEcKgWxcsNI3poB-DJkJhxXjc7R-oZILlBaERpRNqfR-Ch1pvvWuN_9AE651evdGTXr3TqzHVUW8su9hPGMsWqt-iH58RuJ4AiEreHHgdrIPoq3Ie7KCr3v094RvRTo0e</recordid><startdate>201606</startdate><enddate>201606</enddate><creator>Ha, Taekyu</creator><creator>Lou, Zhiyuan</creator><creator>Baek, Seung Joon</creator><creator>Lee, Seong-Ho</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>201606</creationdate><title>Tolfenamic acid downregulates β-catenin in colon cancer</title><author>Ha, Taekyu ; Lou, Zhiyuan ; Baek, Seung Joon ; Lee, Seong-Ho</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c395t-27c4de9ed5658e64336ef6bc4b0b768f09957cee44c604e58f3a3174a176a9bc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - therapeutic use</topic><topic>beta Catenin - genetics</topic><topic>beta Catenin - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Colon cancer</topic><topic>Colonic Neoplasms - drug therapy</topic><topic>Down-Regulation</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Mutant Strains</topic><topic>ortho-Aminobenzoates - therapeutic use</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Smad2</topic><topic>Smad2 Protein - genetics</topic><topic>Smad2 Protein - metabolism</topic><topic>Smad3 Protein - genetics</topic><topic>Smad3 Protein - metabolism</topic><topic>Tolfenamic acid</topic><topic>Vascular Endothelial Growth Factor A - genetics</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>β-catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ha, Taekyu</creatorcontrib><creatorcontrib>Lou, Zhiyuan</creatorcontrib><creatorcontrib>Baek, Seung Joon</creatorcontrib><creatorcontrib>Lee, Seong-Ho</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>International immunopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ha, Taekyu</au><au>Lou, Zhiyuan</au><au>Baek, Seung Joon</au><au>Lee, Seong-Ho</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tolfenamic acid downregulates β-catenin in colon cancer</atitle><jtitle>International immunopharmacology</jtitle><addtitle>Int Immunopharmacol</addtitle><date>2016-06</date><risdate>2016</risdate><volume>35</volume><spage>287</spage><epage>293</epage><pages>287-293</pages><issn>1567-5769</issn><eissn>1878-1705</eissn><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 ApcMin/+ 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.
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| subjects | Animals Anti-Inflammatory Agents, Non-Steroidal - therapeutic use beta Catenin - genetics beta Catenin - metabolism Cell Line, Tumor Colon cancer Colonic Neoplasms - drug therapy Down-Regulation Gene Expression Regulation, Neoplastic Humans Mice Mice, Mutant Strains ortho-Aminobenzoates - therapeutic use Proteasome Endopeptidase Complex - metabolism Smad2 Smad2 Protein - genetics Smad2 Protein - metabolism Smad3 Protein - genetics Smad3 Protein - metabolism Tolfenamic acid Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism β-catenin |
| title | Tolfenamic acid downregulates β-catenin in colon cancer |
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