Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-beta signaling by halofuginone
Radiation-induced fibrosis is an untoward effect of high dose therapeutic and inadvertent exposure to ionizing radiation. Transforming growth factor-beta (TGF-beta) has been proposed to be critical in tissue repair mechanisms resulting from radiation injury. Previously, we showed that interruption o...
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| Veröffentlicht in: | The Journal of biological chemistry 2004-04, Vol.279 (15), p.15167 |
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| creator | Xavier, Sandhya Piek, Ester Fujii, Makiko Javelaud, Delphine Mauviel, Alain Flanders, Kathy C Samuni, Ayelet M Felici, Angelina Reiss, Michael Yarkoni, Shai Sowers, Anastasia Mitchell, James B Roberts, Anita B Russo, Angelo |
| description | Radiation-induced fibrosis is an untoward effect of high dose therapeutic and inadvertent exposure to ionizing radiation. Transforming growth factor-beta (TGF-beta) has been proposed to be critical in tissue repair mechanisms resulting from radiation injury. Previously, we showed that interruption of TGF-beta signaling by deletion of Smad3 results in resistance to radiation-induced injury. In the current study, a small molecular weight molecule, halofuginone (100 nm), is demonstrated by reporter assays to inhibit the TGF-beta signaling pathway, by Northern blotting to elevate inhibitory Smad7 expression within 15 min, and by Western blotting to inhibit formation of phospho-Smad2 and phospho-Smad3 and to decrease cytosolic and membrane TGF-beta type II receptor (TbetaRII). Attenuation of TbetaRII levels was noted as early as 1 h and down-regulation persisted for 24 h. Halofuginone blocked TGF-beta-induced delocalization of tight junction ZO-1, a marker of epidermal mesenchymal transition, in NMuMg mammary epithelial cells and suggest halofuginone may have in vivo anti-fibrogenesis characteristics. After documenting the in vitro cellular effects, halofuginone (intraperitoneum injection of 1, 2.5, or 5 microg/mouse/day) efficacy was assessed using ionizing radiation-induced (single dose, 35 or 45 Gy) hind leg contraction in C3H/Hen mice. Halofuginone treatment alone exerted no toxicity but significantly lessened radiation-induced fibrosis. The effectiveness of radiation treatment (2 gray/day for 5 days) of squamous cell carcinoma (SCC) tumors grown in C3H/Hen was not affected by halofuginone. The results detail the molecular effects of halofuginone on the TGF-beta signal pathway and show that halofuginone may lessen radiation-induced fibrosis in humans. |
| doi_str_mv | 10.1074/jbc.M309798200 |
| format | Article |
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Transforming growth factor-beta (TGF-beta) has been proposed to be critical in tissue repair mechanisms resulting from radiation injury. Previously, we showed that interruption of TGF-beta signaling by deletion of Smad3 results in resistance to radiation-induced injury. In the current study, a small molecular weight molecule, halofuginone (100 nm), is demonstrated by reporter assays to inhibit the TGF-beta signaling pathway, by Northern blotting to elevate inhibitory Smad7 expression within 15 min, and by Western blotting to inhibit formation of phospho-Smad2 and phospho-Smad3 and to decrease cytosolic and membrane TGF-beta type II receptor (TbetaRII). Attenuation of TbetaRII levels was noted as early as 1 h and down-regulation persisted for 24 h. Halofuginone blocked TGF-beta-induced delocalization of tight junction ZO-1, a marker of epidermal mesenchymal transition, in NMuMg mammary epithelial cells and suggest halofuginone may have in vivo anti-fibrogenesis characteristics. After documenting the in vitro cellular effects, halofuginone (intraperitoneum injection of 1, 2.5, or 5 microg/mouse/day) efficacy was assessed using ionizing radiation-induced (single dose, 35 or 45 Gy) hind leg contraction in C3H/Hen mice. Halofuginone treatment alone exerted no toxicity but significantly lessened radiation-induced fibrosis. The effectiveness of radiation treatment (2 gray/day for 5 days) of squamous cell carcinoma (SCC) tumors grown in C3H/Hen was not affected by halofuginone. The results detail the molecular effects of halofuginone on the TGF-beta signal pathway and show that halofuginone may lessen radiation-induced fibrosis in humans.</description><identifier>ISSN: 0021-9258</identifier><identifier>DOI: 10.1074/jbc.M309798200</identifier><identifier>PMID: 14732719</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Blotting, Northern ; Blotting, Western ; Carcinoma, Squamous Cell - drug therapy ; Cell Line ; Cell Line, Tumor ; Cells, Cultured ; COS Cells ; DNA-Binding Proteins - metabolism ; Dose-Response Relationship, Drug ; Down-Regulation ; Fibrosis - metabolism ; Gene Deletion ; Genes, Reporter ; Humans ; Immunoblotting ; MAP Kinase Signaling System ; Mice ; Mice, Inbred C3H ; Microscopy, Confocal ; Microscopy, Fluorescence ; Piperidines ; Plasmids - metabolism ; Protein Synthesis Inhibitors - therapeutic use ; Quinazolines - therapeutic use ; Quinazolinones ; Radiation Pneumonitis - drug therapy ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Smad3 Protein ; Time Factors ; Trans-Activators - metabolism ; Transforming Growth Factor beta - metabolism ; Transforming Growth Factor beta1</subject><ispartof>The Journal of biological chemistry, 2004-04, Vol.279 (15), p.15167</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14732719$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xavier, Sandhya</creatorcontrib><creatorcontrib>Piek, Ester</creatorcontrib><creatorcontrib>Fujii, Makiko</creatorcontrib><creatorcontrib>Javelaud, Delphine</creatorcontrib><creatorcontrib>Mauviel, Alain</creatorcontrib><creatorcontrib>Flanders, Kathy C</creatorcontrib><creatorcontrib>Samuni, Ayelet M</creatorcontrib><creatorcontrib>Felici, Angelina</creatorcontrib><creatorcontrib>Reiss, Michael</creatorcontrib><creatorcontrib>Yarkoni, Shai</creatorcontrib><creatorcontrib>Sowers, Anastasia</creatorcontrib><creatorcontrib>Mitchell, James B</creatorcontrib><creatorcontrib>Roberts, Anita B</creatorcontrib><creatorcontrib>Russo, Angelo</creatorcontrib><title>Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-beta signaling by halofuginone</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Radiation-induced fibrosis is an untoward effect of high dose therapeutic and inadvertent exposure to ionizing radiation. Transforming growth factor-beta (TGF-beta) has been proposed to be critical in tissue repair mechanisms resulting from radiation injury. Previously, we showed that interruption of TGF-beta signaling by deletion of Smad3 results in resistance to radiation-induced injury. In the current study, a small molecular weight molecule, halofuginone (100 nm), is demonstrated by reporter assays to inhibit the TGF-beta signaling pathway, by Northern blotting to elevate inhibitory Smad7 expression within 15 min, and by Western blotting to inhibit formation of phospho-Smad2 and phospho-Smad3 and to decrease cytosolic and membrane TGF-beta type II receptor (TbetaRII). Attenuation of TbetaRII levels was noted as early as 1 h and down-regulation persisted for 24 h. Halofuginone blocked TGF-beta-induced delocalization of tight junction ZO-1, a marker of epidermal mesenchymal transition, in NMuMg mammary epithelial cells and suggest halofuginone may have in vivo anti-fibrogenesis characteristics. After documenting the in vitro cellular effects, halofuginone (intraperitoneum injection of 1, 2.5, or 5 microg/mouse/day) efficacy was assessed using ionizing radiation-induced (single dose, 35 or 45 Gy) hind leg contraction in C3H/Hen mice. Halofuginone treatment alone exerted no toxicity but significantly lessened radiation-induced fibrosis. The effectiveness of radiation treatment (2 gray/day for 5 days) of squamous cell carcinoma (SCC) tumors grown in C3H/Hen was not affected by halofuginone. The results detail the molecular effects of halofuginone on the TGF-beta signal pathway and show that halofuginone may lessen radiation-induced fibrosis in humans.</description><subject>Animals</subject><subject>Blotting, Northern</subject><subject>Blotting, Western</subject><subject>Carcinoma, Squamous Cell - drug therapy</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cells, Cultured</subject><subject>COS Cells</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Down-Regulation</subject><subject>Fibrosis - metabolism</subject><subject>Gene Deletion</subject><subject>Genes, Reporter</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>MAP Kinase Signaling System</subject><subject>Mice</subject><subject>Mice, Inbred C3H</subject><subject>Microscopy, Confocal</subject><subject>Microscopy, Fluorescence</subject><subject>Piperidines</subject><subject>Plasmids - metabolism</subject><subject>Protein Synthesis Inhibitors - therapeutic use</subject><subject>Quinazolines - therapeutic use</subject><subject>Quinazolinones</subject><subject>Radiation Pneumonitis - drug therapy</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Signal Transduction</subject><subject>Smad3 Protein</subject><subject>Time Factors</subject><subject>Trans-Activators - metabolism</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Transforming Growth Factor beta1</subject><issn>0021-9258</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1jz1PwzAYhD2AaCmsjMh_IMVfiWO2qoKCVMQCc_U6thNXiR3ZqVD_PeWjt5xOdzrpQeiOkiUlUjzsdbN840RJVTNCLtCcEEYLxcp6hq5z3pOThKJXaEaF5ExSNUd5NdjexwSTjwFHhxMY_xsKH8yhsQY7r1PMPj9iHzqv_Xk5JQjZxTT40OI2xa-pww6aKaZC2wlw9m2A_qfUR9xBH92h9SEGe4MuHfTZ3v77An0-P32sX4rt--Z1vdoWIyNyKqzh0CgjVG0t504IVYJqCGtODEKUykJdEasr7QxIbSrKiHJlCaCtq5SRfIHu_37Hgx6s2Y3JD5COuzM9_wbC6V5T</recordid><startdate>20040409</startdate><enddate>20040409</enddate><creator>Xavier, Sandhya</creator><creator>Piek, Ester</creator><creator>Fujii, Makiko</creator><creator>Javelaud, Delphine</creator><creator>Mauviel, Alain</creator><creator>Flanders, Kathy C</creator><creator>Samuni, Ayelet M</creator><creator>Felici, Angelina</creator><creator>Reiss, Michael</creator><creator>Yarkoni, Shai</creator><creator>Sowers, Anastasia</creator><creator>Mitchell, James B</creator><creator>Roberts, Anita B</creator><creator>Russo, Angelo</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20040409</creationdate><title>Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-beta signaling by halofuginone</title><author>Xavier, Sandhya ; Piek, Ester ; Fujii, Makiko ; Javelaud, Delphine ; Mauviel, Alain ; Flanders, Kathy C ; Samuni, Ayelet M ; Felici, Angelina ; Reiss, Michael ; Yarkoni, Shai ; Sowers, Anastasia ; Mitchell, James B ; Roberts, Anita B ; Russo, Angelo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p207t-ed3ac9d498ee33f4495a9c02c4914459ea860eb6bfda7bd61209f55aabef69d73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Blotting, Northern</topic><topic>Blotting, Western</topic><topic>Carcinoma, Squamous Cell - drug therapy</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cells, Cultured</topic><topic>COS Cells</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Down-Regulation</topic><topic>Fibrosis - metabolism</topic><topic>Gene Deletion</topic><topic>Genes, Reporter</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>MAP Kinase Signaling System</topic><topic>Mice</topic><topic>Mice, Inbred C3H</topic><topic>Microscopy, Confocal</topic><topic>Microscopy, Fluorescence</topic><topic>Piperidines</topic><topic>Plasmids - metabolism</topic><topic>Protein Synthesis Inhibitors - therapeutic use</topic><topic>Quinazolines - therapeutic use</topic><topic>Quinazolinones</topic><topic>Radiation Pneumonitis - drug therapy</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Signal Transduction</topic><topic>Smad3 Protein</topic><topic>Time Factors</topic><topic>Trans-Activators - metabolism</topic><topic>Transforming Growth Factor beta - metabolism</topic><topic>Transforming Growth Factor beta1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xavier, Sandhya</creatorcontrib><creatorcontrib>Piek, Ester</creatorcontrib><creatorcontrib>Fujii, Makiko</creatorcontrib><creatorcontrib>Javelaud, Delphine</creatorcontrib><creatorcontrib>Mauviel, Alain</creatorcontrib><creatorcontrib>Flanders, Kathy C</creatorcontrib><creatorcontrib>Samuni, Ayelet M</creatorcontrib><creatorcontrib>Felici, Angelina</creatorcontrib><creatorcontrib>Reiss, Michael</creatorcontrib><creatorcontrib>Yarkoni, Shai</creatorcontrib><creatorcontrib>Sowers, Anastasia</creatorcontrib><creatorcontrib>Mitchell, James B</creatorcontrib><creatorcontrib>Roberts, Anita B</creatorcontrib><creatorcontrib>Russo, Angelo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xavier, Sandhya</au><au>Piek, Ester</au><au>Fujii, Makiko</au><au>Javelaud, Delphine</au><au>Mauviel, Alain</au><au>Flanders, Kathy C</au><au>Samuni, Ayelet M</au><au>Felici, Angelina</au><au>Reiss, Michael</au><au>Yarkoni, Shai</au><au>Sowers, Anastasia</au><au>Mitchell, James B</au><au>Roberts, Anita B</au><au>Russo, Angelo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-beta signaling by halofuginone</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2004-04-09</date><risdate>2004</risdate><volume>279</volume><issue>15</issue><spage>15167</spage><pages>15167-</pages><issn>0021-9258</issn><abstract>Radiation-induced fibrosis is an untoward effect of high dose therapeutic and inadvertent exposure to ionizing radiation. Transforming growth factor-beta (TGF-beta) has been proposed to be critical in tissue repair mechanisms resulting from radiation injury. Previously, we showed that interruption of TGF-beta signaling by deletion of Smad3 results in resistance to radiation-induced injury. In the current study, a small molecular weight molecule, halofuginone (100 nm), is demonstrated by reporter assays to inhibit the TGF-beta signaling pathway, by Northern blotting to elevate inhibitory Smad7 expression within 15 min, and by Western blotting to inhibit formation of phospho-Smad2 and phospho-Smad3 and to decrease cytosolic and membrane TGF-beta type II receptor (TbetaRII). Attenuation of TbetaRII levels was noted as early as 1 h and down-regulation persisted for 24 h. Halofuginone blocked TGF-beta-induced delocalization of tight junction ZO-1, a marker of epidermal mesenchymal transition, in NMuMg mammary epithelial cells and suggest halofuginone may have in vivo anti-fibrogenesis characteristics. After documenting the in vitro cellular effects, halofuginone (intraperitoneum injection of 1, 2.5, or 5 microg/mouse/day) efficacy was assessed using ionizing radiation-induced (single dose, 35 or 45 Gy) hind leg contraction in C3H/Hen mice. Halofuginone treatment alone exerted no toxicity but significantly lessened radiation-induced fibrosis. The effectiveness of radiation treatment (2 gray/day for 5 days) of squamous cell carcinoma (SCC) tumors grown in C3H/Hen was not affected by halofuginone. The results detail the molecular effects of halofuginone on the TGF-beta signal pathway and show that halofuginone may lessen radiation-induced fibrosis in humans.</abstract><cop>United States</cop><pmid>14732719</pmid><doi>10.1074/jbc.M309798200</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Blotting, Northern Blotting, Western Carcinoma, Squamous Cell - drug therapy Cell Line Cell Line, Tumor Cells, Cultured COS Cells DNA-Binding Proteins - metabolism Dose-Response Relationship, Drug Down-Regulation Fibrosis - metabolism Gene Deletion Genes, Reporter Humans Immunoblotting MAP Kinase Signaling System Mice Mice, Inbred C3H Microscopy, Confocal Microscopy, Fluorescence Piperidines Plasmids - metabolism Protein Synthesis Inhibitors - therapeutic use Quinazolines - therapeutic use Quinazolinones Radiation Pneumonitis - drug therapy Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Smad3 Protein Time Factors Trans-Activators - metabolism Transforming Growth Factor beta - metabolism Transforming Growth Factor beta1 |
| title | Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-beta signaling by halofuginone |
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