Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells
Salinomycin, an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor, but the biochemical basis for its anticancer effects is not clear. The Wnt/β-catenin signal transduction pathway plays a central role in stem cell development, and its...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2011-08, Vol.108 (32), p.13253-13257 |
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| creator | Lu, Desheng Choi, Michael Y Yu, Jian Castro, Januario E Kipps, Thomas J Carson, Dennis A |
| description | Salinomycin, an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor, but the biochemical basis for its anticancer effects is not clear. The Wnt/β-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down-regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane. |
| doi_str_mv | 10.1073/pnas.1110431108 |
| format | Article |
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The Wnt/β-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down-regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1110431108</identifier><identifier>PMID: 21788521</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Antagonist drugs ; antineoplastic activity ; Apoptosis ; Apoptosis - drug effects ; beta Catenin - metabolism ; Biological Sciences ; Blood cells ; Breast cancer ; breast neoplasms ; Calcium ; Calcium - metabolism ; cell viability ; Cells ; Chronic lymphocytic leukemia ; cyclins ; Down-Regulation - drug effects ; drugs ; fibronectins ; gene expression regulation ; Gene Expression Regulation, Leukemic - drug effects ; genes ; Genes, Neoplasm - genetics ; HEK293 Cells ; Humans ; LDL-Receptor Related Proteins - metabolism ; Leukemia ; Leukemia, Lymphocytic, Chronic, B-Cell - genetics ; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell - pathology ; lipoproteins ; Low Density Lipoprotein Receptor-Related Protein-6 ; Lymphocytes ; lymphocytic leukemia ; neoplasm cells ; nigericin ; Nigericin - pharmacology ; Phosphorylation ; Phosphorylation - drug effects ; plasma membrane ; Plasmids ; potassium ; Pyrans - pharmacology ; salinomycin ; Signal transduction ; Signal Transduction - drug effects ; Stem cells ; Thapsigargin - pharmacology ; toxicity ; Wnt Proteins - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2011-08, Vol.108 (32), p.13253-13257</ispartof><rights>copyright © 1993–2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Aug 9, 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c588t-7291e35dce180ed1e40b67891f72192c02e5a05e85fb3dfac580e68bfe0cb0f73</citedby><cites>FETCH-LOGICAL-c588t-7291e35dce180ed1e40b67891f72192c02e5a05e85fb3dfac580e68bfe0cb0f73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/108/32.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/27979177$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/27979177$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21788521$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lu, Desheng</creatorcontrib><creatorcontrib>Choi, Michael Y</creatorcontrib><creatorcontrib>Yu, Jian</creatorcontrib><creatorcontrib>Castro, Januario E</creatorcontrib><creatorcontrib>Kipps, Thomas J</creatorcontrib><creatorcontrib>Carson, Dennis A</creatorcontrib><title>Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Salinomycin, an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor, but the biochemical basis for its anticancer effects is not clear. The Wnt/β-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down-regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane.</description><subject>Antagonist drugs</subject><subject>antineoplastic activity</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>beta Catenin - metabolism</subject><subject>Biological Sciences</subject><subject>Blood cells</subject><subject>Breast cancer</subject><subject>breast neoplasms</subject><subject>Calcium</subject><subject>Calcium - metabolism</subject><subject>cell viability</subject><subject>Cells</subject><subject>Chronic lymphocytic leukemia</subject><subject>cyclins</subject><subject>Down-Regulation - drug effects</subject><subject>drugs</subject><subject>fibronectins</subject><subject>gene expression regulation</subject><subject>Gene Expression Regulation, Leukemic - drug effects</subject><subject>genes</subject><subject>Genes, Neoplasm - genetics</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>LDL-Receptor Related Proteins - metabolism</subject><subject>Leukemia</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</subject><subject>lipoproteins</subject><subject>Low Density Lipoprotein Receptor-Related Protein-6</subject><subject>Lymphocytes</subject><subject>lymphocytic leukemia</subject><subject>neoplasm cells</subject><subject>nigericin</subject><subject>Nigericin - pharmacology</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>plasma membrane</subject><subject>Plasmids</subject><subject>potassium</subject><subject>Pyrans - pharmacology</subject><subject>salinomycin</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Stem cells</subject><subject>Thapsigargin - pharmacology</subject><subject>toxicity</subject><subject>Wnt Proteins - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkkFv1DAQhS0EokvhzAmIuPSUdsaOY-eChCooSJU4lIqj5TjOrpfEDnFSKf8eR7t0gYtt-X3z5JlnQl4jXCIIdjV4HS8REQqWFvmEbBAqzMuigqdkA0BFLgtanJEXMe4BoOISnpMzikJKTnFD9ne6cz70i3E-c37najfF7Iefsui2ftW2mfZNFm1nzeQebLckrJmNjZkewjCF6GK6ycxuDN6ZrFv6YRfMMq1nO_-0vdOZsV0XX5Jnre6ifXXcz8n950_fr7_kt99uvl5_vM0Nl3LKBa3QMt4YixJsg7aAuhSywlZQrKgBarkGbiVva9a0OlWBLWXdWjA1tIKdkw8H32Gue5t8_DTqTg2j6_W4qKCd-lfxbqe24UEx5CVymgwujgZj-DXbOKnexbUF7W2Yo6pAoEAuy0S-_4_ch3lMY4tKSpYwjpCgqwNkxhDjaNvHpyCoNUW1pqhOKaaKt3938Mj_iS0B2RFYK092UjGqkFHOEvLmgOzjFMaThahEhWKd0ruD3uqg9HZ0Ud3fUcAyfRpAKin7DVbduOc</recordid><startdate>20110809</startdate><enddate>20110809</enddate><creator>Lu, Desheng</creator><creator>Choi, Michael Y</creator><creator>Yu, Jian</creator><creator>Castro, Januario E</creator><creator>Kipps, Thomas J</creator><creator>Carson, Dennis A</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7U7</scope><scope>5PM</scope></search><sort><creationdate>20110809</creationdate><title>Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells</title><author>Lu, Desheng ; 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The Wnt/β-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down-regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21788521</pmid><doi>10.1073/pnas.1110431108</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antagonist drugs antineoplastic activity Apoptosis Apoptosis - drug effects beta Catenin - metabolism Biological Sciences Blood cells Breast cancer breast neoplasms Calcium Calcium - metabolism cell viability Cells Chronic lymphocytic leukemia cyclins Down-Regulation - drug effects drugs fibronectins gene expression regulation Gene Expression Regulation, Leukemic - drug effects genes Genes, Neoplasm - genetics HEK293 Cells Humans LDL-Receptor Related Proteins - metabolism Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - genetics Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Leukemia, Lymphocytic, Chronic, B-Cell - pathology lipoproteins Low Density Lipoprotein Receptor-Related Protein-6 Lymphocytes lymphocytic leukemia neoplasm cells nigericin Nigericin - pharmacology Phosphorylation Phosphorylation - drug effects plasma membrane Plasmids potassium Pyrans - pharmacology salinomycin Signal transduction Signal Transduction - drug effects Stem cells Thapsigargin - pharmacology toxicity Wnt Proteins - metabolism |
| title | Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells |
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