TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells
TLRs function as molecular sensors to detect pathogen-derived products and trigger protective responses ranging from secretion of cytokines that increase the resistance of infected cells and chemokines that recruit immune cells to cell death that limits microbe spreading. Viral dsRNA participate in...
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| Veröffentlicht in: | Journal of Immunology 2006-04, Vol.176 (8), p.4894-4901 |
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| container_title | Journal of Immunology |
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| creator | Salaun, Bruno Coste, Isabelle Rissoan, Marie-Clotilde Lebecque, Serge J Renno, Toufic |
| description | TLRs function as molecular sensors to detect pathogen-derived products and trigger protective responses ranging from secretion of cytokines that increase the resistance of infected cells and chemokines that recruit immune cells to cell death that limits microbe spreading. Viral dsRNA participate in virus-infected cell apoptosis, but the signaling pathway involved remains unclear. In this study we show that synthetic dsRNA induces apoptosis of human breast cancer cells in a TLR3-dependent manner, which involves the molecular adaptor Toll/IL-1R domain-containing adapter inducing IFN-beta and type I IFN autocrine signaling, but occurs independently of the dsRNA-activated kinase. Moreover, detailed molecular analysis of dsRNA-induced cell death established the proapoptotic role of IL-1R-associated kinase-4 and NF-kappaB downstream of TLR3 as well as the activation of the extrinsic caspases. The direct proapoptotic activity of endogenous human TLR3 expressed by cancerous cells reveals a novel aspect of the multiple-faced TLR biology, which may open new clinical prospects for using TLR3 agonists as cytotoxic agents in selected cancers. |
| doi_str_mv | 10.4049/jimmunol.176.8.4894 |
| format | Article |
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Viral dsRNA participate in virus-infected cell apoptosis, but the signaling pathway involved remains unclear. In this study we show that synthetic dsRNA induces apoptosis of human breast cancer cells in a TLR3-dependent manner, which involves the molecular adaptor Toll/IL-1R domain-containing adapter inducing IFN-beta and type I IFN autocrine signaling, but occurs independently of the dsRNA-activated kinase. Moreover, detailed molecular analysis of dsRNA-induced cell death established the proapoptotic role of IL-1R-associated kinase-4 and NF-kappaB downstream of TLR3 as well as the activation of the extrinsic caspases. The direct proapoptotic activity of endogenous human TLR3 expressed by cancerous cells reveals a novel aspect of the multiple-faced TLR biology, which may open new clinical prospects for using TLR3 agonists as cytotoxic agents in selected cancers.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>EISSN: 1365-2567</identifier><identifier>DOI: 10.4049/jimmunol.176.8.4894</identifier><identifier>PMID: 16585585</identifier><language>eng</language><publisher>United States: Am Assoc Immnol</publisher><subject>Apoptosis - immunology ; Base Sequence ; Breast Neoplasms - genetics ; Breast Neoplasms - immunology ; Breast Neoplasms - pathology ; Caspases - metabolism ; Cell Line, Tumor ; DNA, Neoplasm - genetics ; eIF-2 Kinase - metabolism ; Female ; Humans ; Interferon Type I - metabolism ; Interleukin-1 Receptor-Associated Kinases ; Intracellular Signaling Peptides and Proteins - metabolism ; NF-kappa B - metabolism ; Protein-Serine-Threonine Kinases - metabolism ; RNA, Small Interfering - genetics ; Signal Transduction ; TNF Receptor-Associated Factor 6 - metabolism ; Toll-Like Receptor 3 - agonists ; Toll-Like Receptor 3 - genetics ; Toll-Like Receptor 3 - metabolism</subject><ispartof>Journal of Immunology, 2006-04, Vol.176 (8), p.4894-4901</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-fcf1b95fb832de279b465a35746ebe9492866aabd09e85f756099e07220f9c5f3</citedby><cites>FETCH-LOGICAL-c477t-fcf1b95fb832de279b465a35746ebe9492866aabd09e85f756099e07220f9c5f3</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/16585585$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Salaun, Bruno</creatorcontrib><creatorcontrib>Coste, Isabelle</creatorcontrib><creatorcontrib>Rissoan, Marie-Clotilde</creatorcontrib><creatorcontrib>Lebecque, Serge J</creatorcontrib><creatorcontrib>Renno, Toufic</creatorcontrib><title>TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells</title><title>Journal of Immunology</title><addtitle>J Immunol</addtitle><description>TLRs function as molecular sensors to detect pathogen-derived products and trigger protective responses ranging from secretion of cytokines that increase the resistance of infected cells and chemokines that recruit immune cells to cell death that limits microbe spreading. Viral dsRNA participate in virus-infected cell apoptosis, but the signaling pathway involved remains unclear. In this study we show that synthetic dsRNA induces apoptosis of human breast cancer cells in a TLR3-dependent manner, which involves the molecular adaptor Toll/IL-1R domain-containing adapter inducing IFN-beta and type I IFN autocrine signaling, but occurs independently of the dsRNA-activated kinase. Moreover, detailed molecular analysis of dsRNA-induced cell death established the proapoptotic role of IL-1R-associated kinase-4 and NF-kappaB downstream of TLR3 as well as the activation of the extrinsic caspases. The direct proapoptotic activity of endogenous human TLR3 expressed by cancerous cells reveals a novel aspect of the multiple-faced TLR biology, which may open new clinical prospects for using TLR3 agonists as cytotoxic agents in selected cancers.</description><subject>Apoptosis - immunology</subject><subject>Base Sequence</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - immunology</subject><subject>Breast Neoplasms - pathology</subject><subject>Caspases - metabolism</subject><subject>Cell Line, Tumor</subject><subject>DNA, Neoplasm - genetics</subject><subject>eIF-2 Kinase - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>Interferon Type I - metabolism</subject><subject>Interleukin-1 Receptor-Associated Kinases</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>NF-kappa B - metabolism</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>RNA, Small Interfering - genetics</subject><subject>Signal Transduction</subject><subject>TNF Receptor-Associated Factor 6 - metabolism</subject><subject>Toll-Like Receptor 3 - agonists</subject><subject>Toll-Like Receptor 3 - genetics</subject><subject>Toll-Like Receptor 3 - metabolism</subject><issn>0022-1767</issn><issn>1550-6606</issn><issn>1365-2567</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkMtKw0AUhgdRbK0-gSBZ6SpxJnNflnipUBCkrodJOtNOyc1MQujbO6UV3QkHzuJ8_8_hA-AWwYRAIh93rqqGuikTxFkiEiIkOQNTRCmMGYPsHEwhTNM4XPkEXHm_gxAymJJLMEGMChpmCuRq-YGjTNfRk-tM0Zf7aNW5zcZ00bxt2r7xzkeujhZDFZjAFeGSmbL01-DC6tKbm9Oegc-X51W2iJfvr2_ZfBkXhPM-toVFuaQ2Fzhdm5TLnDCqMeWEmdxIIlPBmNb5GkojqOWUQSkN5GkKrSyoxTNwf-xtu-ZrML5XlfNF-EDXphm8YlxgDBH5F0RSYI4kCiA-gkXXeN8Zq9rOVbrbKwTVQa36UauCPCXUQW1I3Z3qh7wy69_MyWUAHo7A1m22Y7CpfKXLMuBIjeP4p-ob_j6Cyw</recordid><startdate>20060415</startdate><enddate>20060415</enddate><creator>Salaun, Bruno</creator><creator>Coste, Isabelle</creator><creator>Rissoan, Marie-Clotilde</creator><creator>Lebecque, Serge J</creator><creator>Renno, Toufic</creator><general>Am Assoc Immnol</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>7T5</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20060415</creationdate><title>TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells</title><author>Salaun, Bruno ; Coste, Isabelle ; Rissoan, Marie-Clotilde ; Lebecque, Serge J ; Renno, Toufic</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-fcf1b95fb832de279b465a35746ebe9492866aabd09e85f756099e07220f9c5f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Apoptosis - immunology</topic><topic>Base Sequence</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - immunology</topic><topic>Breast Neoplasms - pathology</topic><topic>Caspases - metabolism</topic><topic>Cell Line, Tumor</topic><topic>DNA, Neoplasm - genetics</topic><topic>eIF-2 Kinase - metabolism</topic><topic>Female</topic><topic>Humans</topic><topic>Interferon Type I - metabolism</topic><topic>Interleukin-1 Receptor-Associated Kinases</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>NF-kappa B - metabolism</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>RNA, Small Interfering - genetics</topic><topic>Signal Transduction</topic><topic>TNF Receptor-Associated Factor 6 - metabolism</topic><topic>Toll-Like Receptor 3 - agonists</topic><topic>Toll-Like Receptor 3 - genetics</topic><topic>Toll-Like Receptor 3 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Salaun, Bruno</creatorcontrib><creatorcontrib>Coste, Isabelle</creatorcontrib><creatorcontrib>Rissoan, Marie-Clotilde</creatorcontrib><creatorcontrib>Lebecque, Serge J</creatorcontrib><creatorcontrib>Renno, Toufic</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of Immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Salaun, Bruno</au><au>Coste, Isabelle</au><au>Rissoan, Marie-Clotilde</au><au>Lebecque, Serge J</au><au>Renno, Toufic</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells</atitle><jtitle>Journal of Immunology</jtitle><addtitle>J Immunol</addtitle><date>2006-04-15</date><risdate>2006</risdate><volume>176</volume><issue>8</issue><spage>4894</spage><epage>4901</epage><pages>4894-4901</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><eissn>1365-2567</eissn><abstract>TLRs function as molecular sensors to detect pathogen-derived products and trigger protective responses ranging from secretion of cytokines that increase the resistance of infected cells and chemokines that recruit immune cells to cell death that limits microbe spreading. Viral dsRNA participate in virus-infected cell apoptosis, but the signaling pathway involved remains unclear. In this study we show that synthetic dsRNA induces apoptosis of human breast cancer cells in a TLR3-dependent manner, which involves the molecular adaptor Toll/IL-1R domain-containing adapter inducing IFN-beta and type I IFN autocrine signaling, but occurs independently of the dsRNA-activated kinase. Moreover, detailed molecular analysis of dsRNA-induced cell death established the proapoptotic role of IL-1R-associated kinase-4 and NF-kappaB downstream of TLR3 as well as the activation of the extrinsic caspases. The direct proapoptotic activity of endogenous human TLR3 expressed by cancerous cells reveals a novel aspect of the multiple-faced TLR biology, which may open new clinical prospects for using TLR3 agonists as cytotoxic agents in selected cancers.</abstract><cop>United States</cop><pub>Am Assoc Immnol</pub><pmid>16585585</pmid><doi>10.4049/jimmunol.176.8.4894</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Apoptosis - immunology Base Sequence Breast Neoplasms - genetics Breast Neoplasms - immunology Breast Neoplasms - pathology Caspases - metabolism Cell Line, Tumor DNA, Neoplasm - genetics eIF-2 Kinase - metabolism Female Humans Interferon Type I - metabolism Interleukin-1 Receptor-Associated Kinases Intracellular Signaling Peptides and Proteins - metabolism NF-kappa B - metabolism Protein-Serine-Threonine Kinases - metabolism RNA, Small Interfering - genetics Signal Transduction TNF Receptor-Associated Factor 6 - metabolism Toll-Like Receptor 3 - agonists Toll-Like Receptor 3 - genetics Toll-Like Receptor 3 - metabolism |
| title | TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells |
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