Pharmacological Inhibition of TFF3 Enhances Sensitivity of CMS4 Colorectal Carcinoma to 5-Fluorouracil through Inhibition of p44/42 MAPK
Increased expression of trefoil factor 3 (TFF3) has been reported in colorectal carcinoma (CRC), being correlated with distant metastasis and poor clinical outcomes. Amongst the CRC subtypes, mesenchymal (CMS4) CRC is associated with the worst survival outcome. Herein, the functional roles of TFF3 a...
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| Veröffentlicht in: | International journal of molecular sciences 2019-12, Vol.20 (24), p.6215 |
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| creator | Chen, Ru-Mei Chiou, Yi-Shiou Chong, Qing-Yun Poh, Han-Ming Tan, Tuan-Zea Zhang, Meng-Yi Ma, Lan Zhu, Tao Pandey, Vijay Basappa Kumar, Alan Prem Lobie, Peter E |
| description | Increased expression of trefoil factor 3 (TFF3) has been reported in colorectal carcinoma (CRC), being correlated with distant metastasis and poor clinical outcomes. Amongst the CRC subtypes, mesenchymal (CMS4) CRC is associated with the worst survival outcome. Herein, the functional roles of TFF3 and the pharmacological inhibition of TFF3 by a novel specific small molecule TFF3 inhibitor-2-amino-4-(4-(6-fluoro-5-methylpyridin-3-yl)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (AMPC) in CMS4 CRC was explored. Forced expression of TFF3 in CMS4 CRC cells promoted cell proliferation, cell survival, foci formation, invasion, migration, cancer stem cell like behaviour and growth in 3D Matrigel. In contrast, siRNA-mediated depletion of TFF3 or AMPC inhibition of TFF3 in CMS4 CRC cells decreased oncogenic behaviour as indicated by the above cell function assays. AMPC also inhibited tumour growth in vivo. The TFF3-stimulated oncogenic behaviour of CMS4 CRC cells was dependent on TFF3 activation of the p44/42 MAPK (ERK1/2) pathway. Furthermore, the forced expression of TFF3 decreased the sensitivity of CMS4 CRC cells to 5-fluorouracil (5-FU); while depleted TFF3 expression enhanced 5-FU sensitivity in CMS4 CRC cells. 5-FU treatment induced TFF3 expression in CMS4 CRC cells. AMPC, when used in combination with 5-FU in CMS4 CRC cells exhibited a synergistic inhibitory effect. In summary, this study provides functional evidence for TFF3 as a therapeutic target in CMS4 CRC. |
| doi_str_mv | 10.3390/ijms20246215 |
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Amongst the CRC subtypes, mesenchymal (CMS4) CRC is associated with the worst survival outcome. Herein, the functional roles of TFF3 and the pharmacological inhibition of TFF3 by a novel specific small molecule TFF3 inhibitor-2-amino-4-(4-(6-fluoro-5-methylpyridin-3-yl)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (AMPC) in CMS4 CRC was explored. Forced expression of TFF3 in CMS4 CRC cells promoted cell proliferation, cell survival, foci formation, invasion, migration, cancer stem cell like behaviour and growth in 3D Matrigel. In contrast, siRNA-mediated depletion of TFF3 or AMPC inhibition of TFF3 in CMS4 CRC cells decreased oncogenic behaviour as indicated by the above cell function assays. AMPC also inhibited tumour growth in vivo. The TFF3-stimulated oncogenic behaviour of CMS4 CRC cells was dependent on TFF3 activation of the p44/42 MAPK (ERK1/2) pathway. Furthermore, the forced expression of TFF3 decreased the sensitivity of CMS4 CRC cells to 5-fluorouracil (5-FU); while depleted TFF3 expression enhanced 5-FU sensitivity in CMS4 CRC cells. 5-FU treatment induced TFF3 expression in CMS4 CRC cells. AMPC, when used in combination with 5-FU in CMS4 CRC cells exhibited a synergistic inhibitory effect. In summary, this study provides functional evidence for TFF3 as a therapeutic target in CMS4 CRC.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms20246215</identifier><identifier>PMID: 31835445</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>5-Fluorouracil ; Animals ; Apoptosis ; Caco-2 Cells ; Cancer therapies ; Cell adhesion & migration ; Cell cycle ; Cell proliferation ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Chemotherapy ; Classification ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - metabolism ; Colorectal Neoplasms - pathology ; Depletion ; Drug Resistance, Neoplasm - drug effects ; Fluorouracil - pharmacology ; Humans ; Male ; MAP kinase ; MAP Kinase Signaling System - drug effects ; Mesenchyme ; Metastases ; Metastasis ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitogen-Activated Protein Kinase 1 - metabolism ; Mitogen-Activated Protein Kinase 3 - metabolism ; Neoplasm Proteins - antagonists & inhibitors ; Neoplasm Proteins - metabolism ; Nitriles - pharmacology ; Patients ; Pharmacology ; Population ; Proteins ; siRNA ; Stem cells ; Survival ; Trefoil factor ; Trefoil Factor-3 - antagonists & inhibitors ; Trefoil Factor-3 - metabolism ; Tumors</subject><ispartof>International journal of molecular sciences, 2019-12, Vol.20 (24), p.6215</ispartof><rights>2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 by the authors. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c478t-5e7c262202923254c5550934c07a3b4e08154918c26688e6730048382021d6f3</citedby><cites>FETCH-LOGICAL-c478t-5e7c262202923254c5550934c07a3b4e08154918c26688e6730048382021d6f3</cites><orcidid>0000-0002-3754-5712 ; 0000-0001-6624-1593 ; 0000-0002-8844-468X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940926/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940926/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31835445$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Ru-Mei</creatorcontrib><creatorcontrib>Chiou, Yi-Shiou</creatorcontrib><creatorcontrib>Chong, Qing-Yun</creatorcontrib><creatorcontrib>Poh, Han-Ming</creatorcontrib><creatorcontrib>Tan, Tuan-Zea</creatorcontrib><creatorcontrib>Zhang, Meng-Yi</creatorcontrib><creatorcontrib>Ma, Lan</creatorcontrib><creatorcontrib>Zhu, Tao</creatorcontrib><creatorcontrib>Pandey, Vijay</creatorcontrib><creatorcontrib>Basappa</creatorcontrib><creatorcontrib>Kumar, Alan Prem</creatorcontrib><creatorcontrib>Lobie, Peter E</creatorcontrib><title>Pharmacological Inhibition of TFF3 Enhances Sensitivity of CMS4 Colorectal Carcinoma to 5-Fluorouracil through Inhibition of p44/42 MAPK</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Increased expression of trefoil factor 3 (TFF3) has been reported in colorectal carcinoma (CRC), being correlated with distant metastasis and poor clinical outcomes. Amongst the CRC subtypes, mesenchymal (CMS4) CRC is associated with the worst survival outcome. Herein, the functional roles of TFF3 and the pharmacological inhibition of TFF3 by a novel specific small molecule TFF3 inhibitor-2-amino-4-(4-(6-fluoro-5-methylpyridin-3-yl)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (AMPC) in CMS4 CRC was explored. Forced expression of TFF3 in CMS4 CRC cells promoted cell proliferation, cell survival, foci formation, invasion, migration, cancer stem cell like behaviour and growth in 3D Matrigel. In contrast, siRNA-mediated depletion of TFF3 or AMPC inhibition of TFF3 in CMS4 CRC cells decreased oncogenic behaviour as indicated by the above cell function assays. AMPC also inhibited tumour growth in vivo. The TFF3-stimulated oncogenic behaviour of CMS4 CRC cells was dependent on TFF3 activation of the p44/42 MAPK (ERK1/2) pathway. Furthermore, the forced expression of TFF3 decreased the sensitivity of CMS4 CRC cells to 5-fluorouracil (5-FU); while depleted TFF3 expression enhanced 5-FU sensitivity in CMS4 CRC cells. 5-FU treatment induced TFF3 expression in CMS4 CRC cells. AMPC, when used in combination with 5-FU in CMS4 CRC cells exhibited a synergistic inhibitory effect. In summary, this study provides functional evidence for TFF3 as a therapeutic target in CMS4 CRC.</description><subject>5-Fluorouracil</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Caco-2 Cells</subject><subject>Cancer therapies</subject><subject>Cell adhesion & migration</subject><subject>Cell cycle</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Chemotherapy</subject><subject>Classification</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Depletion</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Fluorouracil - pharmacology</subject><subject>Humans</subject><subject>Male</subject><subject>MAP kinase</subject><subject>MAP Kinase Signaling System - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Ru-Mei</au><au>Chiou, Yi-Shiou</au><au>Chong, Qing-Yun</au><au>Poh, Han-Ming</au><au>Tan, Tuan-Zea</au><au>Zhang, Meng-Yi</au><au>Ma, Lan</au><au>Zhu, Tao</au><au>Pandey, Vijay</au><au>Basappa</au><au>Kumar, Alan Prem</au><au>Lobie, Peter E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacological Inhibition of TFF3 Enhances Sensitivity of CMS4 Colorectal Carcinoma to 5-Fluorouracil through Inhibition of p44/42 MAPK</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2019-12-09</date><risdate>2019</risdate><volume>20</volume><issue>24</issue><spage>6215</spage><pages>6215-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Increased expression of trefoil factor 3 (TFF3) has been reported in colorectal carcinoma (CRC), being correlated with distant metastasis and poor clinical outcomes. Amongst the CRC subtypes, mesenchymal (CMS4) CRC is associated with the worst survival outcome. Herein, the functional roles of TFF3 and the pharmacological inhibition of TFF3 by a novel specific small molecule TFF3 inhibitor-2-amino-4-(4-(6-fluoro-5-methylpyridin-3-yl)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (AMPC) in CMS4 CRC was explored. Forced expression of TFF3 in CMS4 CRC cells promoted cell proliferation, cell survival, foci formation, invasion, migration, cancer stem cell like behaviour and growth in 3D Matrigel. In contrast, siRNA-mediated depletion of TFF3 or AMPC inhibition of TFF3 in CMS4 CRC cells decreased oncogenic behaviour as indicated by the above cell function assays. AMPC also inhibited tumour growth in vivo. The TFF3-stimulated oncogenic behaviour of CMS4 CRC cells was dependent on TFF3 activation of the p44/42 MAPK (ERK1/2) pathway. Furthermore, the forced expression of TFF3 decreased the sensitivity of CMS4 CRC cells to 5-fluorouracil (5-FU); while depleted TFF3 expression enhanced 5-FU sensitivity in CMS4 CRC cells. 5-FU treatment induced TFF3 expression in CMS4 CRC cells. AMPC, when used in combination with 5-FU in CMS4 CRC cells exhibited a synergistic inhibitory effect. In summary, this study provides functional evidence for TFF3 as a therapeutic target in CMS4 CRC.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>31835445</pmid><doi>10.3390/ijms20246215</doi><orcidid>https://orcid.org/0000-0002-3754-5712</orcidid><orcidid>https://orcid.org/0000-0001-6624-1593</orcidid><orcidid>https://orcid.org/0000-0002-8844-468X</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of molecular sciences, 2019-12, Vol.20 (24), p.6215 |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | 5-Fluorouracil Animals Apoptosis Caco-2 Cells Cancer therapies Cell adhesion & migration Cell cycle Cell proliferation Cell Proliferation - drug effects Cell Survival - drug effects Chemotherapy Classification Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - drug therapy Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Depletion Drug Resistance, Neoplasm - drug effects Fluorouracil - pharmacology Humans Male MAP kinase MAP Kinase Signaling System - drug effects Mesenchyme Metastases Metastasis Mice Mice, Inbred BALB C Mice, Nude Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - metabolism Nitriles - pharmacology Patients Pharmacology Population Proteins siRNA Stem cells Survival Trefoil factor Trefoil Factor-3 - antagonists & inhibitors Trefoil Factor-3 - metabolism Tumors |
| title | Pharmacological Inhibition of TFF3 Enhances Sensitivity of CMS4 Colorectal Carcinoma to 5-Fluorouracil through Inhibition of p44/42 MAPK |
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