STAT3 Cyclic Decoy Demonstrates Robust Antitumor Effects in Non-Small Cell Lung Cancer
Constitutively activated STAT3 plays a critical role in non-small cell lung carcinoma (NSCLC) progression by mediating proliferation and survival. STAT3 activation in normal cells is transient, making it an attractive target for NSCLC therapy. The therapeutic potential of blocking STAT3 in NSCLC was...
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Veröffentlicht in: | Molecular cancer therapeutics 2018-09, Vol.17 (9), p.1917-1926 |
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description | Constitutively activated STAT3 plays a critical role in non-small cell lung carcinoma (NSCLC) progression by mediating proliferation and survival. STAT3 activation in normal cells is transient, making it an attractive target for NSCLC therapy. The therapeutic potential of blocking STAT3 in NSCLC was assessed utilizing a decoy approach by ligating a double-stranded 15-mer oligonucleotide that corresponds to the STAT3 response element of STAT3-target genes, to produce a cyclic STAT3 decoy (CS3D). The decoy was evaluated using NSCLC cells containing either wild-type EGFR (201T) or mutant EGFR with an additional EGFRi resistance mutation (H1975). These cells are resistant to EGFR inhibitors and require an alternate therapeutic approach. CS3D activity was compared with an inactive cyclic control oligonucleotide (CS3M) that differs by a single base pair, rendering it unable to bind to STAT3 protein. Transfection of 0.3 μmol/L of CS3D caused a 50% inhibition in proliferation in 201T and H1975 cells, relative to CS3M, and a 2-fold increase in apoptotic cells. Toxicity was minimal in normal cells. CS3D treatment caused a significant reduction of mRNA and protein expression of the STAT3 target gene c-Myc and inhibited colony formation by 70%. The active decoy decreased the nuclear pool of STAT3 compared with the mutant. In a xenograft model, treatments with CS3D (5 mg/kg) caused a potent 96.5% and 81.7% reduction in tumor growth in 201T (
< 0.007) and H1975 models (
< 0.0001), respectively, and reduced c-Myc and p-STAT3 proteins. Targeting STAT3 with the cyclic decoy could be an effective therapeutic strategy for NSCLC.
. |
doi_str_mv | 10.1158/1535-7163.MCT-17-1194 |
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< 0.007) and H1975 models (
< 0.0001), respectively, and reduced c-Myc and p-STAT3 proteins. Targeting STAT3 with the cyclic decoy could be an effective therapeutic strategy for NSCLC.
.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-17-1194</identifier><identifier>PMID: 29891486</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Apoptosis - drug effects ; Apoptosis - genetics ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - metabolism ; Cell Line, Tumor ; ErbB Receptors - genetics ; ErbB Receptors - metabolism ; Female ; Gene Expression Regulation, Neoplastic - drug effects ; Humans ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Mice, Nude ; Mutation ; Oligonucleotides, Antisense - genetics ; Oligonucleotides, Antisense - pharmacology ; STAT3 Transcription Factor - genetics ; STAT3 Transcription Factor - metabolism ; Xenograft Model Antitumor Assays - methods</subject><ispartof>Molecular cancer therapeutics, 2018-09, Vol.17 (9), p.1917-1926</ispartof><rights>2018 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-1457d20397879cd3382e05b4ba26bc02285c400db5ebf1b2674725cdea314bb83</citedby><cites>FETCH-LOGICAL-c411t-1457d20397879cd3382e05b4ba26bc02285c400db5ebf1b2674725cdea314bb83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,3357,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29891486$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Njatcha, Christian</creatorcontrib><creatorcontrib>Farooqui, Mariya</creatorcontrib><creatorcontrib>Kornberg, Adam</creatorcontrib><creatorcontrib>Johnson, Daniel E</creatorcontrib><creatorcontrib>Grandis, Jennifer R</creatorcontrib><creatorcontrib>Siegfried, Jill M</creatorcontrib><title>STAT3 Cyclic Decoy Demonstrates Robust Antitumor Effects in Non-Small Cell Lung Cancer</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Constitutively activated STAT3 plays a critical role in non-small cell lung carcinoma (NSCLC) progression by mediating proliferation and survival. STAT3 activation in normal cells is transient, making it an attractive target for NSCLC therapy. The therapeutic potential of blocking STAT3 in NSCLC was assessed utilizing a decoy approach by ligating a double-stranded 15-mer oligonucleotide that corresponds to the STAT3 response element of STAT3-target genes, to produce a cyclic STAT3 decoy (CS3D). The decoy was evaluated using NSCLC cells containing either wild-type EGFR (201T) or mutant EGFR with an additional EGFRi resistance mutation (H1975). These cells are resistant to EGFR inhibitors and require an alternate therapeutic approach. CS3D activity was compared with an inactive cyclic control oligonucleotide (CS3M) that differs by a single base pair, rendering it unable to bind to STAT3 protein. Transfection of 0.3 μmol/L of CS3D caused a 50% inhibition in proliferation in 201T and H1975 cells, relative to CS3M, and a 2-fold increase in apoptotic cells. Toxicity was minimal in normal cells. CS3D treatment caused a significant reduction of mRNA and protein expression of the STAT3 target gene c-Myc and inhibited colony formation by 70%. The active decoy decreased the nuclear pool of STAT3 compared with the mutant. In a xenograft model, treatments with CS3D (5 mg/kg) caused a potent 96.5% and 81.7% reduction in tumor growth in 201T (
< 0.007) and H1975 models (
< 0.0001), respectively, and reduced c-Myc and p-STAT3 proteins. Targeting STAT3 with the cyclic decoy could be an effective therapeutic strategy for NSCLC.
.</description><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Cell Line, Tumor</subject><subject>ErbB Receptors - genetics</subject><subject>ErbB Receptors - metabolism</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Humans</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Mice, Nude</subject><subject>Mutation</subject><subject>Oligonucleotides, Antisense - genetics</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><subject>STAT3 Transcription Factor - genetics</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Xenograft Model Antitumor Assays - methods</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkNtOwzAMhiMEYjB4BFBeoCPOoU1vkKYyDtIAiRVuoyZNR1GbTk2LtLenZTDBjW3Z_n9bH0IXQGYAQl6BYCKIIGSzxyQNIAoAYn6AToa-DKQAfvhd73Ym6NT7D0JAxhSO0YTGMgYuwxP0tkrnKcPJ1lSlwTfWNNsh1o3zXZt11uOXRve-w3PXlV1fNy1eFIU1ncelw0-NC1Z1VlU4sUNY9m6Nk8wZ256hoyKrvD3_yVP0ertIk_tg-Xz3kMyXgeEAXQBcRDklLI5kFJucMUktEZrrjIbaEEqlMJyQXAurC9A0jHhEhcltxoBrLdkUXe98N72ubW6sG96u1KYt66zdqiYr1f-JK9_VuvlUIVABcTgYiJ2BaRvvW1vstUDUCFqNENUIUQ2gFURqBD3oLv8e3qt-ybIvvBh6Cw</recordid><startdate>20180901</startdate><enddate>20180901</enddate><creator>Njatcha, Christian</creator><creator>Farooqui, Mariya</creator><creator>Kornberg, Adam</creator><creator>Johnson, Daniel E</creator><creator>Grandis, Jennifer R</creator><creator>Siegfried, Jill M</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><scope>5PM</scope></search><sort><creationdate>20180901</creationdate><title>STAT3 Cyclic Decoy Demonstrates Robust Antitumor Effects in Non-Small Cell Lung Cancer</title><author>Njatcha, Christian ; 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STAT3 activation in normal cells is transient, making it an attractive target for NSCLC therapy. The therapeutic potential of blocking STAT3 in NSCLC was assessed utilizing a decoy approach by ligating a double-stranded 15-mer oligonucleotide that corresponds to the STAT3 response element of STAT3-target genes, to produce a cyclic STAT3 decoy (CS3D). The decoy was evaluated using NSCLC cells containing either wild-type EGFR (201T) or mutant EGFR with an additional EGFRi resistance mutation (H1975). These cells are resistant to EGFR inhibitors and require an alternate therapeutic approach. CS3D activity was compared with an inactive cyclic control oligonucleotide (CS3M) that differs by a single base pair, rendering it unable to bind to STAT3 protein. Transfection of 0.3 μmol/L of CS3D caused a 50% inhibition in proliferation in 201T and H1975 cells, relative to CS3M, and a 2-fold increase in apoptotic cells. Toxicity was minimal in normal cells. CS3D treatment caused a significant reduction of mRNA and protein expression of the STAT3 target gene c-Myc and inhibited colony formation by 70%. The active decoy decreased the nuclear pool of STAT3 compared with the mutant. In a xenograft model, treatments with CS3D (5 mg/kg) caused a potent 96.5% and 81.7% reduction in tumor growth in 201T (
< 0.007) and H1975 models (
< 0.0001), respectively, and reduced c-Myc and p-STAT3 proteins. Targeting STAT3 with the cyclic decoy could be an effective therapeutic strategy for NSCLC.
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subjects | Animals Apoptosis - drug effects Apoptosis - genetics Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Cell Line, Tumor ErbB Receptors - genetics ErbB Receptors - metabolism Female Gene Expression Regulation, Neoplastic - drug effects Humans Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - metabolism Mice, Nude Mutation Oligonucleotides, Antisense - genetics Oligonucleotides, Antisense - pharmacology STAT3 Transcription Factor - genetics STAT3 Transcription Factor - metabolism Xenograft Model Antitumor Assays - methods |
title | STAT3 Cyclic Decoy Demonstrates Robust Antitumor Effects in Non-Small Cell Lung Cancer |
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