Phenylmethimazole Decreases Toll-Like Receptor 3 and Noncanonical Wnt5a Expression in Pancreatic Cancer and Melanoma Together with Tumor Cell Growth and Migration
Purpose: To evaluate whether ( a ) Wnt5a expression in pancreatic cancer and malignant melanoma cells might be associated with constitutive levels of Toll-like receptor 3 (TLR3) and/or TLR3 signaling; ( b ) phenylmethimazole (C10), a novel TLR signaling inhibitor, could decrease constitutive Wnt5a a...
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| Veröffentlicht in: | Clinical cancer research 2009-06, Vol.15 (12), p.4114-4122 |
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| creator | Schwartz, Anthony L Malgor, Ramiro Dickerson, Eric Weeraratna, Ashani T Slominski, Andrzej Wortsman, Jacobo Harii, Norikazu Kohn, Aimee D Moon, Randall T Schwartz, Frank L Goetz, Douglas J Kohn, Leonard D McCall, Kelly D |
| description | Purpose: To evaluate whether ( a ) Wnt5a expression in pancreatic cancer and malignant melanoma cells might be associated with constitutive levels of Toll-like
receptor 3 (TLR3) and/or TLR3 signaling; ( b ) phenylmethimazole (C10), a novel TLR signaling inhibitor, could decrease constitutive Wnt5a and TLR3 levels together with
cell growth and migration; and ( c ) the efficacy of C10 as a potential inhibitor of pancreatic cancer and malignant melanoma cell growth in vivo .
Experimental Design: We used a variety of molecular biology techniques including but not limited to PCR, Western blotting, and ELISA to evaluate
the presence of constitutively activated TLR3/Wnt5a expression and signaling. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide-based technology and scratch assays were used to evaluate inhibition of cell growth and migration, respectively. TLR3
regulation of cell growth was confirmed using small interfering RNA technology. Nude and severe combined immunodeficient mice
were implanted with human pancreatic cancer and/or melanoma cells and the effects of C10 on tumor growth were evaluated.
Results: We show that constitutive TLR3 expression is associated with constitutive Wnt5a in human pancreatic cancer and malignant
melanoma cell lines, that C10 can decrease constitutive TLR3/Wnt5a expression and signaling, suggesting that they are interrelated
signal systems, and that C10 inhibits growth and migration in both of these cancer cell lines. We also report that C10 is
effective at inhibiting human pancreatic cancer and malignant melanoma tumor growth in vivo in nude or severe combined immunodeficient mice and associate this with inhibition of signal transducers and activators of
transcription 3 activation.
Conclusions: C10 may have potential therapeutic applicability in pancreatic cancer and malignant melanoma. |
| doi_str_mv | 10.1158/1078-0432.CCR-09-0005 |
| format | Article |
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receptor 3 (TLR3) and/or TLR3 signaling; ( b ) phenylmethimazole (C10), a novel TLR signaling inhibitor, could decrease constitutive Wnt5a and TLR3 levels together with
cell growth and migration; and ( c ) the efficacy of C10 as a potential inhibitor of pancreatic cancer and malignant melanoma cell growth in vivo .
Experimental Design: We used a variety of molecular biology techniques including but not limited to PCR, Western blotting, and ELISA to evaluate
the presence of constitutively activated TLR3/Wnt5a expression and signaling. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide-based technology and scratch assays were used to evaluate inhibition of cell growth and migration, respectively. TLR3
regulation of cell growth was confirmed using small interfering RNA technology. Nude and severe combined immunodeficient mice
were implanted with human pancreatic cancer and/or melanoma cells and the effects of C10 on tumor growth were evaluated.
Results: We show that constitutive TLR3 expression is associated with constitutive Wnt5a in human pancreatic cancer and malignant
melanoma cell lines, that C10 can decrease constitutive TLR3/Wnt5a expression and signaling, suggesting that they are interrelated
signal systems, and that C10 inhibits growth and migration in both of these cancer cell lines. We also report that C10 is
effective at inhibiting human pancreatic cancer and malignant melanoma tumor growth in vivo in nude or severe combined immunodeficient mice and associate this with inhibition of signal transducers and activators of
transcription 3 activation.
Conclusions: C10 may have potential therapeutic applicability in pancreatic cancer and malignant melanoma.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-09-0005</identifier><identifier>PMID: 19470740</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject><![CDATA[Animals ; Antithyroid Agents - pharmacology ; Cell Line, Tumor ; Chemokine CXCL10 - antagonists & inhibitors ; Chemokine CXCL10 - metabolism ; Gene Knockdown Techniques ; Humans ; Interferon-beta - antagonists & inhibitors ; Interferon-beta - metabolism ; Interleukin-6 - antagonists & inhibitors ; Interleukin-6 - metabolism ; Melanoma - drug therapy ; Melanoma - metabolism ; Melanoma - pathology ; Methimazole - analogs & derivatives ; Methimazole - pharmacology ; Mice ; Mice, Nude ; Mice, SCID ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; phenylmethimazole ; Proto-Oncogene Proteins - antagonists & inhibitors ; Proto-Oncogene Proteins - metabolism ; RNA, Small Interfering - metabolism ; Signal Transduction - drug effects ; Signal Transduction - physiology ; Skin Neoplasms - drug therapy ; Skin Neoplasms - metabolism ; Skin Neoplasms - pathology ; STAT3 Transcription Factor - antagonists & inhibitors ; STAT3 Transcription Factor - metabolism ; Thiones - pharmacology ; Toll-Like Receptor 3 - antagonists & inhibitors ; Toll-Like Receptor 3 - genetics ; Toll-Like Receptor 3 - metabolism ; Toll-like receptors ; Wnt Proteins - antagonists & inhibitors ; Wnt Proteins - metabolism ; Wnt-5a Protein ; Wnt5a]]></subject><ispartof>Clinical cancer research, 2009-06, Vol.15 (12), p.4114-4122</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c388t-c346629e53b8fe54843d1a3610bba30e036bd3c8d1b0ca81ebfb9d48bf0fe9e73</citedby><cites>FETCH-LOGICAL-c388t-c346629e53b8fe54843d1a3610bba30e036bd3c8d1b0ca81ebfb9d48bf0fe9e73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19470740$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schwartz, Anthony L</creatorcontrib><creatorcontrib>Malgor, Ramiro</creatorcontrib><creatorcontrib>Dickerson, Eric</creatorcontrib><creatorcontrib>Weeraratna, Ashani T</creatorcontrib><creatorcontrib>Slominski, Andrzej</creatorcontrib><creatorcontrib>Wortsman, Jacobo</creatorcontrib><creatorcontrib>Harii, Norikazu</creatorcontrib><creatorcontrib>Kohn, Aimee D</creatorcontrib><creatorcontrib>Moon, Randall T</creatorcontrib><creatorcontrib>Schwartz, Frank L</creatorcontrib><creatorcontrib>Goetz, Douglas J</creatorcontrib><creatorcontrib>Kohn, Leonard D</creatorcontrib><creatorcontrib>McCall, Kelly D</creatorcontrib><title>Phenylmethimazole Decreases Toll-Like Receptor 3 and Noncanonical Wnt5a Expression in Pancreatic Cancer and Melanoma Together with Tumor Cell Growth and Migration</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Purpose: To evaluate whether ( a ) Wnt5a expression in pancreatic cancer and malignant melanoma cells might be associated with constitutive levels of Toll-like
receptor 3 (TLR3) and/or TLR3 signaling; ( b ) phenylmethimazole (C10), a novel TLR signaling inhibitor, could decrease constitutive Wnt5a and TLR3 levels together with
cell growth and migration; and ( c ) the efficacy of C10 as a potential inhibitor of pancreatic cancer and malignant melanoma cell growth in vivo .
Experimental Design: We used a variety of molecular biology techniques including but not limited to PCR, Western blotting, and ELISA to evaluate
the presence of constitutively activated TLR3/Wnt5a expression and signaling. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide-based technology and scratch assays were used to evaluate inhibition of cell growth and migration, respectively. TLR3
regulation of cell growth was confirmed using small interfering RNA technology. Nude and severe combined immunodeficient mice
were implanted with human pancreatic cancer and/or melanoma cells and the effects of C10 on tumor growth were evaluated.
Results: We show that constitutive TLR3 expression is associated with constitutive Wnt5a in human pancreatic cancer and malignant
melanoma cell lines, that C10 can decrease constitutive TLR3/Wnt5a expression and signaling, suggesting that they are interrelated
signal systems, and that C10 inhibits growth and migration in both of these cancer cell lines. We also report that C10 is
effective at inhibiting human pancreatic cancer and malignant melanoma tumor growth in vivo in nude or severe combined immunodeficient mice and associate this with inhibition of signal transducers and activators of
transcription 3 activation.
Conclusions: C10 may have potential therapeutic applicability in pancreatic cancer and malignant melanoma.</description><subject>Animals</subject><subject>Antithyroid Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Chemokine CXCL10 - antagonists & inhibitors</subject><subject>Chemokine CXCL10 - metabolism</subject><subject>Gene Knockdown Techniques</subject><subject>Humans</subject><subject>Interferon-beta - antagonists & inhibitors</subject><subject>Interferon-beta - metabolism</subject><subject>Interleukin-6 - antagonists & inhibitors</subject><subject>Interleukin-6 - metabolism</subject><subject>Melanoma - drug therapy</subject><subject>Melanoma - metabolism</subject><subject>Melanoma - pathology</subject><subject>Methimazole - analogs & derivatives</subject><subject>Methimazole - pharmacology</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Mice, SCID</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>phenylmethimazole</subject><subject>Proto-Oncogene Proteins - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>Skin Neoplasms - drug therapy</subject><subject>Skin Neoplasms - metabolism</subject><subject>Skin Neoplasms - pathology</subject><subject>STAT3 Transcription Factor - antagonists & inhibitors</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Thiones - pharmacology</subject><subject>Toll-Like Receptor 3 - antagonists & inhibitors</subject><subject>Toll-Like Receptor 3 - genetics</subject><subject>Toll-Like Receptor 3 - metabolism</subject><subject>Toll-like receptors</subject><subject>Wnt Proteins - antagonists & inhibitors</subject><subject>Wnt Proteins - metabolism</subject><subject>Wnt-5a Protein</subject><subject>Wnt5a</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkc1u1DAUhSMEoj_wCCCvkFikXMd24ixRKC3SAFU1iKXlODcTQ2JP7YyG8jg8Kc7MIDa2dfWdc61zsuwVhStKhXxHoZI5cFZcNc19DnUOAOJJdk6FqHJWlOJpev9jzrKLGH8AUE6BP8_OaM0rqDicZ3_uBnSP44TzYCf9249IPqAJqCNGsvbjmK_sTyT3aHA7-0AY0a4jX7wz2nlnjR7JdzcLTa5_bQPGaL0j1pE77RaT2RrSpCeGg-wzjkk16WS8SQvTdG_ngax3U3JucBzJTfD7NDnAdhOSgXcvsme9HiO-PN2X2beP1-vmNl99vfnUvF_lhkk5p5OXZVGjYK3sUXDJWUc1Kym0rWaAwMq2Y0Z2tAWjJcW2b-uOy7aHHmus2GX25ui7Df5hh3FWk40m_Uo79LuoyopVkhcsgeIImuBjDNirbUjhhUdFQS3lqCV4tQSvUjkKarWUk3SvTwt27YTdf9WpjQS8PQKD3Qx7G1CZQ3gpWNTBDIoKRQvFKeXsL2YYm_4</recordid><startdate>20090615</startdate><enddate>20090615</enddate><creator>Schwartz, Anthony L</creator><creator>Malgor, Ramiro</creator><creator>Dickerson, Eric</creator><creator>Weeraratna, Ashani T</creator><creator>Slominski, Andrzej</creator><creator>Wortsman, Jacobo</creator><creator>Harii, Norikazu</creator><creator>Kohn, Aimee D</creator><creator>Moon, Randall T</creator><creator>Schwartz, Frank L</creator><creator>Goetz, Douglas J</creator><creator>Kohn, Leonard D</creator><creator>McCall, Kelly D</creator><general>American Association for Cancer Research</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></search><sort><creationdate>20090615</creationdate><title>Phenylmethimazole Decreases Toll-Like Receptor 3 and Noncanonical Wnt5a Expression in Pancreatic Cancer and Melanoma Together with Tumor Cell Growth and Migration</title><author>Schwartz, Anthony L ; Malgor, Ramiro ; Dickerson, Eric ; Weeraratna, Ashani T ; Slominski, Andrzej ; Wortsman, Jacobo ; Harii, Norikazu ; Kohn, Aimee D ; Moon, Randall T ; Schwartz, Frank L ; Goetz, Douglas J ; Kohn, Leonard D ; McCall, Kelly D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c388t-c346629e53b8fe54843d1a3610bba30e036bd3c8d1b0ca81ebfb9d48bf0fe9e73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Antithyroid Agents - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Chemokine CXCL10 - antagonists & inhibitors</topic><topic>Chemokine CXCL10 - metabolism</topic><topic>Gene Knockdown Techniques</topic><topic>Humans</topic><topic>Interferon-beta - antagonists & inhibitors</topic><topic>Interferon-beta - metabolism</topic><topic>Interleukin-6 - antagonists & inhibitors</topic><topic>Interleukin-6 - metabolism</topic><topic>Melanoma - drug therapy</topic><topic>Melanoma - metabolism</topic><topic>Melanoma - pathology</topic><topic>Methimazole - analogs & derivatives</topic><topic>Methimazole - pharmacology</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Mice, SCID</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>phenylmethimazole</topic><topic>Proto-Oncogene Proteins - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><topic>Skin Neoplasms - drug therapy</topic><topic>Skin Neoplasms - metabolism</topic><topic>Skin Neoplasms - pathology</topic><topic>STAT3 Transcription Factor - antagonists & inhibitors</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Thiones - pharmacology</topic><topic>Toll-Like Receptor 3 - antagonists & inhibitors</topic><topic>Toll-Like Receptor 3 - genetics</topic><topic>Toll-Like Receptor 3 - metabolism</topic><topic>Toll-like receptors</topic><topic>Wnt Proteins - antagonists & inhibitors</topic><topic>Wnt Proteins - metabolism</topic><topic>Wnt-5a Protein</topic><topic>Wnt5a</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schwartz, Anthony L</creatorcontrib><creatorcontrib>Malgor, Ramiro</creatorcontrib><creatorcontrib>Dickerson, Eric</creatorcontrib><creatorcontrib>Weeraratna, Ashani T</creatorcontrib><creatorcontrib>Slominski, Andrzej</creatorcontrib><creatorcontrib>Wortsman, Jacobo</creatorcontrib><creatorcontrib>Harii, Norikazu</creatorcontrib><creatorcontrib>Kohn, Aimee D</creatorcontrib><creatorcontrib>Moon, Randall T</creatorcontrib><creatorcontrib>Schwartz, Frank L</creatorcontrib><creatorcontrib>Goetz, Douglas J</creatorcontrib><creatorcontrib>Kohn, Leonard D</creatorcontrib><creatorcontrib>McCall, Kelly D</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><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schwartz, Anthony L</au><au>Malgor, Ramiro</au><au>Dickerson, Eric</au><au>Weeraratna, Ashani T</au><au>Slominski, Andrzej</au><au>Wortsman, Jacobo</au><au>Harii, Norikazu</au><au>Kohn, Aimee D</au><au>Moon, Randall T</au><au>Schwartz, Frank L</au><au>Goetz, Douglas J</au><au>Kohn, Leonard D</au><au>McCall, Kelly D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phenylmethimazole Decreases Toll-Like Receptor 3 and Noncanonical Wnt5a Expression in Pancreatic Cancer and Melanoma Together with Tumor Cell Growth and Migration</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2009-06-15</date><risdate>2009</risdate><volume>15</volume><issue>12</issue><spage>4114</spage><epage>4122</epage><pages>4114-4122</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Purpose: To evaluate whether ( a ) Wnt5a expression in pancreatic cancer and malignant melanoma cells might be associated with constitutive levels of Toll-like
receptor 3 (TLR3) and/or TLR3 signaling; ( b ) phenylmethimazole (C10), a novel TLR signaling inhibitor, could decrease constitutive Wnt5a and TLR3 levels together with
cell growth and migration; and ( c ) the efficacy of C10 as a potential inhibitor of pancreatic cancer and malignant melanoma cell growth in vivo .
Experimental Design: We used a variety of molecular biology techniques including but not limited to PCR, Western blotting, and ELISA to evaluate
the presence of constitutively activated TLR3/Wnt5a expression and signaling. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide-based technology and scratch assays were used to evaluate inhibition of cell growth and migration, respectively. TLR3
regulation of cell growth was confirmed using small interfering RNA technology. Nude and severe combined immunodeficient mice
were implanted with human pancreatic cancer and/or melanoma cells and the effects of C10 on tumor growth were evaluated.
Results: We show that constitutive TLR3 expression is associated with constitutive Wnt5a in human pancreatic cancer and malignant
melanoma cell lines, that C10 can decrease constitutive TLR3/Wnt5a expression and signaling, suggesting that they are interrelated
signal systems, and that C10 inhibits growth and migration in both of these cancer cell lines. We also report that C10 is
effective at inhibiting human pancreatic cancer and malignant melanoma tumor growth in vivo in nude or severe combined immunodeficient mice and associate this with inhibition of signal transducers and activators of
transcription 3 activation.
Conclusions: C10 may have potential therapeutic applicability in pancreatic cancer and malignant melanoma.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>19470740</pmid><doi>10.1158/1078-0432.CCR-09-0005</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-0432 |
| ispartof | Clinical cancer research, 2009-06, Vol.15 (12), p.4114-4122 |
| issn | 1078-0432 1557-3265 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_67378423 |
| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Antithyroid Agents - pharmacology Cell Line, Tumor Chemokine CXCL10 - antagonists & inhibitors Chemokine CXCL10 - metabolism Gene Knockdown Techniques Humans Interferon-beta - antagonists & inhibitors Interferon-beta - metabolism Interleukin-6 - antagonists & inhibitors Interleukin-6 - metabolism Melanoma - drug therapy Melanoma - metabolism Melanoma - pathology Methimazole - analogs & derivatives Methimazole - pharmacology Mice Mice, Nude Mice, SCID Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology phenylmethimazole Proto-Oncogene Proteins - antagonists & inhibitors Proto-Oncogene Proteins - metabolism RNA, Small Interfering - metabolism Signal Transduction - drug effects Signal Transduction - physiology Skin Neoplasms - drug therapy Skin Neoplasms - metabolism Skin Neoplasms - pathology STAT3 Transcription Factor - antagonists & inhibitors STAT3 Transcription Factor - metabolism Thiones - pharmacology Toll-Like Receptor 3 - antagonists & inhibitors Toll-Like Receptor 3 - genetics Toll-Like Receptor 3 - metabolism Toll-like receptors Wnt Proteins - antagonists & inhibitors Wnt Proteins - metabolism Wnt-5a Protein Wnt5a |
| title | Phenylmethimazole Decreases Toll-Like Receptor 3 and Noncanonical Wnt5a Expression in Pancreatic Cancer and Melanoma Together with Tumor Cell Growth and Migration |
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