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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:The Journal of biological chemistry 2008-04, Vol.283 (17), p.11752-11762
Hauptverfasser: Nishimura, Shinpei, Takahashi, Shunsuke, Kamikatahira, Hiromi, Kuroki, Yuko, Jaalouk, Diana E., O'Brien, Susan, Koivunen, Erkki, Arap, Wadih, Pasqualini, Renata, Nakayama, Hitoshi, Kuniyasu, Akihiko
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 11762
container_issue 17
container_start_page 11752
container_title The Journal of biological chemistry
container_volume 283
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
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3762554</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0021925820619706</els_id><sourcerecordid>69111673</sourcerecordid><originalsourceid>FETCH-LOGICAL-c587t-b7889b2e76c0eefe1e1ce89dd5d16eec82aea6656f080625c6465aff87285d1e3</originalsourceid><addsrcrecordid>eNqFkc1v1DAQxS0EokvhyhF8QNyy2E78kQsSWkFB2gokWsTNcpxJ4pLEW9vbav_7usqKwgHhyxz8mzdv5iH0kpI1JbJ6d9XY9bkkSlU1I-QRWlGiyqLk9OdjtCKE0aJmXJ2gZzFekfyqmj5FJ1SxjKtyhX5s_NS42SQfnBnxhQk9JDf32Hc4DYDPjQ1-52ZvD8knZ_E3k4Zbc8BuxlvY_4LJGWzmFm8P027wk8EbGMf4HD3pzBjhxbGeostPHy82n4vt17Mvmw_bwnIlU9FIpeqGgRSWAHRAgVpQddvylgoAq5gBIwQXHVFEMG5FJbjpOiWZygiUp-j9orvbNxO0FuYUzKh3wU0mHLQ3Tv_9M7tB9_5GlzLL8SoLvD0KBH-9h5j05KLNK5gZ_D5qUVNKhSz_C-ZzVlwxmcH1AubDxRig--2GEn2fmc6Z6YfMcsOrP3d4wI8hZeDNAgyuH25dAN04bweYNFOlplJTKjnL2OsF64zXpg8u6svvjNCS5FGCqHtraiEgR3LjIOhoHcwW2ixqk269-5fJO-nfvFg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>20845827</pqid></control><display><type>article</type><title>Combinatorial Targeting of the Macropinocytotic Pathway in Leukemia and Lymphoma Cells</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><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</creator><creatorcontrib>Nishimura, Shinpei ; Takahashi, Shunsuke ; Kamikatahira, Hiromi ; Kuroki, Yuko ; Jaalouk, Diana E. ; O'Brien, Susan ; Koivunen, Erkki ; Arap, Wadih ; Pasqualini, Renata ; Nakayama, Hitoshi ; Kuniyasu, Akihiko</creatorcontrib><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><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>
fulltext fulltext
identifier ISSN: 0021-9258
ispartof The Journal of biological chemistry, 2008-04, Vol.283 (17), p.11752-11762
issn 0021-9258
1083-351X
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3762554
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection
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
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T14%3A49%3A31IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Combinatorial%20Targeting%20of%20the%20Macropinocytotic%20Pathway%20in%20Leukemia%20and%20Lymphoma%20Cells&rft.jtitle=The%20Journal%20of%20biological%20chemistry&rft.au=Nishimura,%20Shinpei&rft.date=2008-04-25&rft.volume=283&rft.issue=17&rft.spage=11752&rft.epage=11762&rft.pages=11752-11762&rft.issn=0021-9258&rft.eissn=1083-351X&rft_id=info:doi/10.1074/jbc.M708849200&rft_dat=%3Cproquest_pubme%3E69111673%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=20845827&rft_id=info:pmid/18292083&rft_els_id=S0021925820619706&rfr_iscdi=true