Effect of focal adhesion kinase (FAK) downregulation with FAK antisense oligonucleotides and 5-fluorouracil on the viability of melanoma cell lines
Inhibition of focal adhesion kinase (FAK), a non-receptor tyrosine kinase linked to tumour cell survival, causes cell rounding, loss of adhesion and apoptosis in human cancer cell lines. In this study, we tested antisense oligonucleotide inhibitors of FAK, in combination with 5-fluorouracil (5-FU),...
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| Veröffentlicht in: | Melanoma research 2005-10, Vol.15 (5), p.357-362 |
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| creator | Smith, Charles S Golubovskaya, Vita M Peck, Erin Xu, Li-Hui Monia, Brett P Yang, Xihui Cance, William G |
| description | Inhibition of focal adhesion kinase (FAK), a non-receptor tyrosine kinase linked to tumour cell survival, causes cell rounding, loss of adhesion and apoptosis in human cancer cell lines. In this study, we tested antisense oligonucleotide inhibitors of FAK, in combination with 5-fluorouracil (5-FU), to increase its sensitivity in human melanoma cell lines. Antisense oligonucleotides directed to the 5' mRNA sequence of FAK and missense control oligonucleotides were used. In BL melanoma cells, treatment with FAK antisense oligonucleotide was associated with a 2.5-fold increase in cell death compared with treatment with control oligonucleotide (33+/-2% vs. 13+/-3%, P |
| doi_str_mv | 10.1097/00008390-200510000-00003 |
| format | Article |
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In this study, we tested antisense oligonucleotide inhibitors of FAK, in combination with 5-fluorouracil (5-FU), to increase its sensitivity in human melanoma cell lines. Antisense oligonucleotides directed to the 5' mRNA sequence of FAK and missense control oligonucleotides were used. In BL melanoma cells, treatment with FAK antisense oligonucleotide was associated with a 2.5-fold increase in cell death compared with treatment with control oligonucleotide (33+/-2% vs. 13+/-3%, P<0.0001). 5-FU alone had no effect on BL cells (4.4% cell death, P=0.15). The addition of 5-FU after antisense oligonucleotide resulted in a significant synergistic increase in cell death equal to 69+/-2% compared with treatments with antisense oligonucleotide alone, 5-FU alone and control oligonucleotide (P<0.0001). Similar results were found in the C8161 melanoma cell line. In both cell lines, reduction in cell viability was accompanied by an increased loss of adhesion and increased apoptosis that was proportional to the decrease in viability. Treatment with antisense oligonucleotide plus 5-FU resulted in significantly decreased p125FAK expression in both C8161 and BL melanoma cell lines, demonstrated by Western blot analyses. These data show that the downregulation of FAK by antisense oligonucleotide combined with 5-FU chemotherapy results in a greater loss of adhesion and greater apoptosis in melanoma cells than treatment with either agent alone, suggesting that the combination may be a potential therapeutic agent for human melanoma in vivo.</description><identifier>ISSN: 0960-8931</identifier><identifier>DOI: 10.1097/00008390-200510000-00003</identifier><identifier>PMID: 16179862</identifier><language>eng</language><publisher>England</publisher><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Apoptosis - drug effects ; Apoptosis - genetics ; Cell Line, Tumor ; Down-Regulation ; Drug Synergism ; Fluorouracil - administration & dosage ; Fluorouracil - pharmacology ; Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors ; Focal Adhesion Protein-Tyrosine Kinases - biosynthesis ; Focal Adhesion Protein-Tyrosine Kinases - genetics ; Humans ; Melanoma - drug therapy ; Melanoma - enzymology ; Melanoma - genetics ; Melanoma - therapy ; Oligonucleotides, Antisense - administration & dosage ; Oligonucleotides, Antisense - genetics ; Oligonucleotides, Antisense - pharmacology</subject><ispartof>Melanoma research, 2005-10, Vol.15 (5), p.357-362</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c313t-3b6b5148a76c84973aa04b9fd58ac2ac95a7c45298d3fe3706a019a5146877f93</citedby><cites>FETCH-LOGICAL-c313t-3b6b5148a76c84973aa04b9fd58ac2ac95a7c45298d3fe3706a019a5146877f93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16179862$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Smith, Charles S</creatorcontrib><creatorcontrib>Golubovskaya, Vita M</creatorcontrib><creatorcontrib>Peck, Erin</creatorcontrib><creatorcontrib>Xu, Li-Hui</creatorcontrib><creatorcontrib>Monia, Brett P</creatorcontrib><creatorcontrib>Yang, Xihui</creatorcontrib><creatorcontrib>Cance, William G</creatorcontrib><title>Effect of focal adhesion kinase (FAK) downregulation with FAK antisense oligonucleotides and 5-fluorouracil on the viability of melanoma cell lines</title><title>Melanoma research</title><addtitle>Melanoma Res</addtitle><description>Inhibition of focal adhesion kinase (FAK), a non-receptor tyrosine kinase linked to tumour cell survival, causes cell rounding, loss of adhesion and apoptosis in human cancer cell lines. In this study, we tested antisense oligonucleotide inhibitors of FAK, in combination with 5-fluorouracil (5-FU), to increase its sensitivity in human melanoma cell lines. Antisense oligonucleotides directed to the 5' mRNA sequence of FAK and missense control oligonucleotides were used. In BL melanoma cells, treatment with FAK antisense oligonucleotide was associated with a 2.5-fold increase in cell death compared with treatment with control oligonucleotide (33+/-2% vs. 13+/-3%, P<0.0001). 5-FU alone had no effect on BL cells (4.4% cell death, P=0.15). The addition of 5-FU after antisense oligonucleotide resulted in a significant synergistic increase in cell death equal to 69+/-2% compared with treatments with antisense oligonucleotide alone, 5-FU alone and control oligonucleotide (P<0.0001). Similar results were found in the C8161 melanoma cell line. In both cell lines, reduction in cell viability was accompanied by an increased loss of adhesion and increased apoptosis that was proportional to the decrease in viability. Treatment with antisense oligonucleotide plus 5-FU resulted in significantly decreased p125FAK expression in both C8161 and BL melanoma cell lines, demonstrated by Western blot analyses. These data show that the downregulation of FAK by antisense oligonucleotide combined with 5-FU chemotherapy results in a greater loss of adhesion and greater apoptosis in melanoma cells than treatment with either agent alone, suggesting that the combination may be a potential therapeutic agent for human melanoma in vivo.</description><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Cell Line, Tumor</subject><subject>Down-Regulation</subject><subject>Drug Synergism</subject><subject>Fluorouracil - administration & dosage</subject><subject>Fluorouracil - pharmacology</subject><subject>Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Focal Adhesion Protein-Tyrosine Kinases - biosynthesis</subject><subject>Focal Adhesion Protein-Tyrosine Kinases - genetics</subject><subject>Humans</subject><subject>Melanoma - drug therapy</subject><subject>Melanoma - enzymology</subject><subject>Melanoma - genetics</subject><subject>Melanoma - therapy</subject><subject>Oligonucleotides, Antisense - administration & dosage</subject><subject>Oligonucleotides, Antisense - genetics</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><issn>0960-8931</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkM9OwzAMxnMAsTF4BZQjHApJ0zbJcZo2QEziAufKTZMtkCZT0zLtOXhhWsYfH2zZn3-29CGEKbmlRPI7MoRgkiQpITkdu2RM7ARNiSxIIiSjE3Qe4xshlLOcnaEJLSiXokin6HNpjFYdDgaboMBhqLc62uDxu_UQNb5ezZ9ucB32vtWb3kE3anvbbfEgYPCdjdoPe8HZTfC9cjp0ttZxkGqcJ8b1oQ19C8o6PJDdVuMPC5V1tjuMXxvtwIcGsNLOYWe9jhfo1ICL-vKnztDravmyeEjWz_ePi_k6UYyyLmFVUeU0E8ALJTLJGQDJKmnqXIBKQckcuMryVIqaGc04KYBQCQNSCM6NZDMkjndVG2JstSl3rW2gPZSUlKO35a-35Z-33yM2oFdHdNdXja7_wR9j2RdjPHhP</recordid><startdate>20051001</startdate><enddate>20051001</enddate><creator>Smith, Charles S</creator><creator>Golubovskaya, Vita M</creator><creator>Peck, Erin</creator><creator>Xu, Li-Hui</creator><creator>Monia, Brett P</creator><creator>Yang, Xihui</creator><creator>Cance, William G</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20051001</creationdate><title>Effect of focal adhesion kinase (FAK) downregulation with FAK antisense oligonucleotides and 5-fluorouracil on the viability of melanoma cell lines</title><author>Smith, Charles S ; Golubovskaya, Vita M ; Peck, Erin ; Xu, Li-Hui ; Monia, Brett P ; Yang, Xihui ; Cance, William G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c313t-3b6b5148a76c84973aa04b9fd58ac2ac95a7c45298d3fe3706a019a5146877f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>Cell Line, Tumor</topic><topic>Down-Regulation</topic><topic>Drug Synergism</topic><topic>Fluorouracil - administration & dosage</topic><topic>Fluorouracil - pharmacology</topic><topic>Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Focal Adhesion Protein-Tyrosine Kinases - biosynthesis</topic><topic>Focal Adhesion Protein-Tyrosine Kinases - genetics</topic><topic>Humans</topic><topic>Melanoma - drug therapy</topic><topic>Melanoma - enzymology</topic><topic>Melanoma - genetics</topic><topic>Melanoma - therapy</topic><topic>Oligonucleotides, Antisense - administration & dosage</topic><topic>Oligonucleotides, Antisense - genetics</topic><topic>Oligonucleotides, Antisense - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Smith, Charles S</creatorcontrib><creatorcontrib>Golubovskaya, Vita M</creatorcontrib><creatorcontrib>Peck, Erin</creatorcontrib><creatorcontrib>Xu, Li-Hui</creatorcontrib><creatorcontrib>Monia, Brett P</creatorcontrib><creatorcontrib>Yang, Xihui</creatorcontrib><creatorcontrib>Cance, William G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Melanoma research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Smith, Charles S</au><au>Golubovskaya, Vita M</au><au>Peck, Erin</au><au>Xu, Li-Hui</au><au>Monia, Brett P</au><au>Yang, Xihui</au><au>Cance, William G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of focal adhesion kinase (FAK) downregulation with FAK antisense oligonucleotides and 5-fluorouracil on the viability of melanoma cell lines</atitle><jtitle>Melanoma research</jtitle><addtitle>Melanoma Res</addtitle><date>2005-10-01</date><risdate>2005</risdate><volume>15</volume><issue>5</issue><spage>357</spage><epage>362</epage><pages>357-362</pages><issn>0960-8931</issn><abstract>Inhibition of focal adhesion kinase (FAK), a non-receptor tyrosine kinase linked to tumour cell survival, causes cell rounding, loss of adhesion and apoptosis in human cancer cell lines. In this study, we tested antisense oligonucleotide inhibitors of FAK, in combination with 5-fluorouracil (5-FU), to increase its sensitivity in human melanoma cell lines. Antisense oligonucleotides directed to the 5' mRNA sequence of FAK and missense control oligonucleotides were used. In BL melanoma cells, treatment with FAK antisense oligonucleotide was associated with a 2.5-fold increase in cell death compared with treatment with control oligonucleotide (33+/-2% vs. 13+/-3%, P<0.0001). 5-FU alone had no effect on BL cells (4.4% cell death, P=0.15). The addition of 5-FU after antisense oligonucleotide resulted in a significant synergistic increase in cell death equal to 69+/-2% compared with treatments with antisense oligonucleotide alone, 5-FU alone and control oligonucleotide (P<0.0001). Similar results were found in the C8161 melanoma cell line. In both cell lines, reduction in cell viability was accompanied by an increased loss of adhesion and increased apoptosis that was proportional to the decrease in viability. Treatment with antisense oligonucleotide plus 5-FU resulted in significantly decreased p125FAK expression in both C8161 and BL melanoma cell lines, demonstrated by Western blot analyses. These data show that the downregulation of FAK by antisense oligonucleotide combined with 5-FU chemotherapy results in a greater loss of adhesion and greater apoptosis in melanoma cells than treatment with either agent alone, suggesting that the combination may be a potential therapeutic agent for human melanoma in vivo.</abstract><cop>England</cop><pmid>16179862</pmid><doi>10.1097/00008390-200510000-00003</doi><tpages>6</tpages></addata></record> |
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| subjects | Antineoplastic Combined Chemotherapy Protocols - pharmacology Apoptosis - drug effects Apoptosis - genetics Cell Line, Tumor Down-Regulation Drug Synergism Fluorouracil - administration & dosage Fluorouracil - pharmacology Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors Focal Adhesion Protein-Tyrosine Kinases - biosynthesis Focal Adhesion Protein-Tyrosine Kinases - genetics Humans Melanoma - drug therapy Melanoma - enzymology Melanoma - genetics Melanoma - therapy Oligonucleotides, Antisense - administration & dosage Oligonucleotides, Antisense - genetics Oligonucleotides, Antisense - pharmacology |
| title | Effect of focal adhesion kinase (FAK) downregulation with FAK antisense oligonucleotides and 5-fluorouracil on the viability of melanoma cell lines |
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