Combinatorial Targeting of the Macropinocytotic Pathway in Leukemia and Lymphoma Cells
Ligand-directed delivery of agents to leukemia and lymphoma cells has the potential to yield new mechanistic disease insights and targeted therapies. Here we set out to target the macropinocytotic pathway with a combinatorial approach. From the screening of acute T-lymphoblastic leukemia Molt-4 cell...
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Veröffentlicht in: | The Journal of biological chemistry 2008-04, Vol.283 (17), p.11752-11762 |
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creator | Nishimura, Shinpei Takahashi, Shunsuke Kamikatahira, Hiromi Kuroki, Yuko Jaalouk, Diana E. O'Brien, Susan Koivunen, Erkki Arap, Wadih Pasqualini, Renata Nakayama, Hitoshi Kuniyasu, Akihiko |
description | Ligand-directed delivery of agents to leukemia and lymphoma cells has the potential to yield new mechanistic disease insights and targeted therapies. Here we set out to target the macropinocytotic pathway with a combinatorial approach. From the screening of acute T-lymphoblastic leukemia Molt-4 cells with a random phage-display peptide library, we isolated a phage displaying the sequence CAYHRLRRC. This peptide contains a lymph node-homing motif (Cys-Ala-Tyr) and a cell-penetrating motif (Arg-Leu-Arg-Arg). Binding of this ligand-directed phage to a large panel of leukemia/lymphoma cells and to patient-derived samples was much higher than to non-leukemia control cells. CAYHRLRRC phage internalization into Molt-4 cells is both energy- and temperature-dependent. Flow cytometry with fluorescein-labeled peptide and endocytosis blocking with specific inhibitors revealed that CAYHRLRRC is indeed taken up through macropinocytosis in Molt-4 and K562 human leukemia cells. Unexpectedly, the cell surface receptor for the CAYHRLRRC peptide is not a heparan sulfate proteoglycan as it would be predicted for other cell-penetrating peptides. Confirming this interpretation, a CAYHRLRRC-directed peptidomimetic-induced cell death in all the leukemia and lymphoma cells was evaluated, whereas a control transactivator of transcription protein (tat)-directed proapoptotic peptidomimetic was non-selective. In summary, the targeting peptide CAYHRLRRC is selectively internalized through macropinocytosis in leukemia and lymphoma cells and has potential as a drug lead for ligand-directed anti-leukemia therapies. |
doi_str_mv | 10.1074/jbc.M708849200 |
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Here we set out to target the macropinocytotic pathway with a combinatorial approach. From the screening of acute T-lymphoblastic leukemia Molt-4 cells with a random phage-display peptide library, we isolated a phage displaying the sequence CAYHRLRRC. This peptide contains a lymph node-homing motif (Cys-Ala-Tyr) and a cell-penetrating motif (Arg-Leu-Arg-Arg). Binding of this ligand-directed phage to a large panel of leukemia/lymphoma cells and to patient-derived samples was much higher than to non-leukemia control cells. CAYHRLRRC phage internalization into Molt-4 cells is both energy- and temperature-dependent. Flow cytometry with fluorescein-labeled peptide and endocytosis blocking with specific inhibitors revealed that CAYHRLRRC is indeed taken up through macropinocytosis in Molt-4 and K562 human leukemia cells. Unexpectedly, the cell surface receptor for the CAYHRLRRC peptide is not a heparan sulfate proteoglycan as it would be predicted for other cell-penetrating peptides. Confirming this interpretation, a CAYHRLRRC-directed peptidomimetic-induced cell death in all the leukemia and lymphoma cells was evaluated, whereas a control transactivator of transcription protein (tat)-directed proapoptotic peptidomimetic was non-selective. In summary, the targeting peptide CAYHRLRRC is selectively internalized through macropinocytosis in leukemia and lymphoma cells and has potential as a drug lead for ligand-directed anti-leukemia therapies.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M708849200</identifier><identifier>PMID: 18292083</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antineoplastic Agents - pharmacology ; Catalysis ; Cell Line, Tumor ; Cell Survival ; Chemistry, Pharmaceutical - methods ; Drug Design ; Enzyme Catalysis and Regulation ; Gene Expression Regulation, Leukemic ; Humans ; K562 Cells ; Leukemia - metabolism ; Ligands ; Lymphoma - metabolism ; Peptide Library ; Peptides - chemistry ; Pinocytosis</subject><ispartof>The Journal of biological chemistry, 2008-04, Vol.283 (17), p.11752-11762</ispartof><rights>2008 © 2008 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2008 by The American Society for Biochemistry and Molecular Biology, Inc. 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c587t-b7889b2e76c0eefe1e1ce89dd5d16eec82aea6656f080625c6465aff87285d1e3</citedby><cites>FETCH-LOGICAL-c587t-b7889b2e76c0eefe1e1ce89dd5d16eec82aea6656f080625c6465aff87285d1e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762554/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762554/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18292083$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nishimura, Shinpei</creatorcontrib><creatorcontrib>Takahashi, Shunsuke</creatorcontrib><creatorcontrib>Kamikatahira, Hiromi</creatorcontrib><creatorcontrib>Kuroki, Yuko</creatorcontrib><creatorcontrib>Jaalouk, Diana E.</creatorcontrib><creatorcontrib>O'Brien, Susan</creatorcontrib><creatorcontrib>Koivunen, Erkki</creatorcontrib><creatorcontrib>Arap, Wadih</creatorcontrib><creatorcontrib>Pasqualini, Renata</creatorcontrib><creatorcontrib>Nakayama, Hitoshi</creatorcontrib><creatorcontrib>Kuniyasu, Akihiko</creatorcontrib><title>Combinatorial Targeting of the Macropinocytotic Pathway in Leukemia and Lymphoma Cells</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Ligand-directed delivery of agents to leukemia and lymphoma cells has the potential to yield new mechanistic disease insights and targeted therapies. Here we set out to target the macropinocytotic pathway with a combinatorial approach. From the screening of acute T-lymphoblastic leukemia Molt-4 cells with a random phage-display peptide library, we isolated a phage displaying the sequence CAYHRLRRC. This peptide contains a lymph node-homing motif (Cys-Ala-Tyr) and a cell-penetrating motif (Arg-Leu-Arg-Arg). Binding of this ligand-directed phage to a large panel of leukemia/lymphoma cells and to patient-derived samples was much higher than to non-leukemia control cells. CAYHRLRRC phage internalization into Molt-4 cells is both energy- and temperature-dependent. Flow cytometry with fluorescein-labeled peptide and endocytosis blocking with specific inhibitors revealed that CAYHRLRRC is indeed taken up through macropinocytosis in Molt-4 and K562 human leukemia cells. Unexpectedly, the cell surface receptor for the CAYHRLRRC peptide is not a heparan sulfate proteoglycan as it would be predicted for other cell-penetrating peptides. Confirming this interpretation, a CAYHRLRRC-directed peptidomimetic-induced cell death in all the leukemia and lymphoma cells was evaluated, whereas a control transactivator of transcription protein (tat)-directed proapoptotic peptidomimetic was non-selective. In summary, the targeting peptide CAYHRLRRC is selectively internalized through macropinocytosis in leukemia and lymphoma cells and has potential as a drug lead for ligand-directed anti-leukemia therapies.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Catalysis</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival</subject><subject>Chemistry, Pharmaceutical - methods</subject><subject>Drug Design</subject><subject>Enzyme Catalysis and Regulation</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>Humans</subject><subject>K562 Cells</subject><subject>Leukemia - metabolism</subject><subject>Ligands</subject><subject>Lymphoma - metabolism</subject><subject>Peptide Library</subject><subject>Peptides - chemistry</subject><subject>Pinocytosis</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1v1DAQxS0EokvhyhF8QNyy2E78kQsSWkFB2gokWsTNcpxJ4pLEW9vbav_7usqKwgHhyxz8mzdv5iH0kpI1JbJ6d9XY9bkkSlU1I-QRWlGiyqLk9OdjtCKE0aJmXJ2gZzFekfyqmj5FJ1SxjKtyhX5s_NS42SQfnBnxhQk9JDf32Hc4DYDPjQ1-52ZvD8knZ_E3k4Zbc8BuxlvY_4LJGWzmFm8P027wk8EbGMf4HD3pzBjhxbGeostPHy82n4vt17Mvmw_bwnIlU9FIpeqGgRSWAHRAgVpQddvylgoAq5gBIwQXHVFEMG5FJbjpOiWZygiUp-j9orvbNxO0FuYUzKh3wU0mHLQ3Tv_9M7tB9_5GlzLL8SoLvD0KBH-9h5j05KLNK5gZ_D5qUVNKhSz_C-ZzVlwxmcH1AubDxRig--2GEn2fmc6Z6YfMcsOrP3d4wI8hZeDNAgyuH25dAN04bweYNFOlplJTKjnL2OsF64zXpg8u6svvjNCS5FGCqHtraiEgR3LjIOhoHcwW2ixqk269-5fJO-nfvFg</recordid><startdate>20080425</startdate><enddate>20080425</enddate><creator>Nishimura, Shinpei</creator><creator>Takahashi, Shunsuke</creator><creator>Kamikatahira, Hiromi</creator><creator>Kuroki, Yuko</creator><creator>Jaalouk, Diana E.</creator><creator>O'Brien, Susan</creator><creator>Koivunen, Erkki</creator><creator>Arap, Wadih</creator><creator>Pasqualini, Renata</creator><creator>Nakayama, Hitoshi</creator><creator>Kuniyasu, Akihiko</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><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>7T5</scope><scope>7TM</scope><scope>H94</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20080425</creationdate><title>Combinatorial Targeting of the Macropinocytotic Pathway in Leukemia and Lymphoma Cells</title><author>Nishimura, Shinpei ; Takahashi, Shunsuke ; Kamikatahira, Hiromi ; Kuroki, Yuko ; Jaalouk, Diana E. ; O'Brien, Susan ; Koivunen, Erkki ; Arap, Wadih ; Pasqualini, Renata ; Nakayama, Hitoshi ; Kuniyasu, Akihiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c587t-b7889b2e76c0eefe1e1ce89dd5d16eec82aea6656f080625c6465aff87285d1e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Catalysis</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival</topic><topic>Chemistry, Pharmaceutical - methods</topic><topic>Drug Design</topic><topic>Enzyme Catalysis and Regulation</topic><topic>Gene Expression Regulation, Leukemic</topic><topic>Humans</topic><topic>K562 Cells</topic><topic>Leukemia - metabolism</topic><topic>Ligands</topic><topic>Lymphoma - metabolism</topic><topic>Peptide Library</topic><topic>Peptides - chemistry</topic><topic>Pinocytosis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nishimura, Shinpei</creatorcontrib><creatorcontrib>Takahashi, Shunsuke</creatorcontrib><creatorcontrib>Kamikatahira, Hiromi</creatorcontrib><creatorcontrib>Kuroki, Yuko</creatorcontrib><creatorcontrib>Jaalouk, Diana E.</creatorcontrib><creatorcontrib>O'Brien, Susan</creatorcontrib><creatorcontrib>Koivunen, Erkki</creatorcontrib><creatorcontrib>Arap, Wadih</creatorcontrib><creatorcontrib>Pasqualini, Renata</creatorcontrib><creatorcontrib>Nakayama, Hitoshi</creatorcontrib><creatorcontrib>Kuniyasu, Akihiko</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><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>Nucleic Acids Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nishimura, Shinpei</au><au>Takahashi, Shunsuke</au><au>Kamikatahira, Hiromi</au><au>Kuroki, Yuko</au><au>Jaalouk, Diana E.</au><au>O'Brien, Susan</au><au>Koivunen, Erkki</au><au>Arap, Wadih</au><au>Pasqualini, Renata</au><au>Nakayama, Hitoshi</au><au>Kuniyasu, Akihiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combinatorial Targeting of the Macropinocytotic Pathway in Leukemia and Lymphoma Cells</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2008-04-25</date><risdate>2008</risdate><volume>283</volume><issue>17</issue><spage>11752</spage><epage>11762</epage><pages>11752-11762</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Ligand-directed delivery of agents to leukemia and lymphoma cells has the potential to yield new mechanistic disease insights and targeted therapies. Here we set out to target the macropinocytotic pathway with a combinatorial approach. From the screening of acute T-lymphoblastic leukemia Molt-4 cells with a random phage-display peptide library, we isolated a phage displaying the sequence CAYHRLRRC. This peptide contains a lymph node-homing motif (Cys-Ala-Tyr) and a cell-penetrating motif (Arg-Leu-Arg-Arg). Binding of this ligand-directed phage to a large panel of leukemia/lymphoma cells and to patient-derived samples was much higher than to non-leukemia control cells. CAYHRLRRC phage internalization into Molt-4 cells is both energy- and temperature-dependent. Flow cytometry with fluorescein-labeled peptide and endocytosis blocking with specific inhibitors revealed that CAYHRLRRC is indeed taken up through macropinocytosis in Molt-4 and K562 human leukemia cells. Unexpectedly, the cell surface receptor for the CAYHRLRRC peptide is not a heparan sulfate proteoglycan as it would be predicted for other cell-penetrating peptides. Confirming this interpretation, a CAYHRLRRC-directed peptidomimetic-induced cell death in all the leukemia and lymphoma cells was evaluated, whereas a control transactivator of transcription protein (tat)-directed proapoptotic peptidomimetic was non-selective. In summary, the targeting peptide CAYHRLRRC is selectively internalized through macropinocytosis in leukemia and lymphoma cells and has potential as a drug lead for ligand-directed anti-leukemia therapies.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18292083</pmid><doi>10.1074/jbc.M708849200</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Antineoplastic Agents - pharmacology Catalysis Cell Line, Tumor Cell Survival Chemistry, Pharmaceutical - methods Drug Design Enzyme Catalysis and Regulation Gene Expression Regulation, Leukemic Humans K562 Cells Leukemia - metabolism Ligands Lymphoma - metabolism Peptide Library Peptides - chemistry Pinocytosis |
title | Combinatorial Targeting of the Macropinocytotic Pathway in Leukemia and Lymphoma Cells |
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