Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells
The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of epithelial–mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 c...
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| Veröffentlicht in: | Oncogene 2013-01, Vol.32 (2), p.209-221 |
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| creator | Jung, M-J Rho, J-K Kim, Y-M Jung, J E Jin, Y B Ko, Y-G Lee, J-S Lee, S-J Lee, J C Park, M-J |
| description | The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of epithelial–mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity
in vitro
and tumorigenicity
in vivo
. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance
in vitro
and exhibited stronger tumorigenic potential
in vivo
than CXCR4− cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC. |
| doi_str_mv | 10.1038/onc.2012.37 |
| format | Article |
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in vitro
and tumorigenicity
in vivo
. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance
in vitro
and exhibited stronger tumorigenic potential
in vivo
than CXCR4− cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2012.37</identifier><identifier>PMID: 22370645</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>1-Phosphatidylinositol 3-kinase ; 631/67/1059/2326 ; 631/67/71 ; 631/80/86 ; 692/699/67/1612/1350 ; AKT protein ; Animals ; Apoptosis ; Cancer ; Cancer cells ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - metabolism ; Carcinoma, Non-Small-Cell Lung - pathology ; Care and treatment ; Cell Biology ; Cell Line, Tumor ; Chemokine CXCL12 - metabolism ; CXCR4 protein ; Data processing ; Development and progression ; Drug resistance ; Drug Resistance, Neoplasm ; Female ; Heterocyclic Compounds - pharmacology ; Human Genetics ; Humans ; Internal Medicine ; Lung cancer ; Lung cancer, Non-small cell ; Lung Neoplasms - drug therapy ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Medicine ; Medicine & Public Health ; Mice ; Mice, Nude ; Mice, SCID ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - physiology ; Non-small cell lung carcinoma ; Oncology ; original-article ; Phosphatidylinositol 3-Kinase - metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Phosphorylation ; Proto-Oncogene Proteins c-akt - metabolism ; PTEN Phosphohydrolase - genetics ; PTEN Phosphohydrolase - metabolism ; PTEN protein ; Pyridines - pharmacology ; Receptors, CXCR4 - antagonists & inhibitors ; Receptors, CXCR4 - genetics ; Receptors, CXCR4 - metabolism ; RNA Interference ; RNA, Small Interfering ; SDF-1 protein ; Secretion ; Signal Transduction ; siRNA ; Stat3 protein ; STAT3 Transcription Factor - antagonists & inhibitors ; STAT3 Transcription Factor - genetics ; STAT3 Transcription Factor - metabolism ; Stem cells ; TOR protein ; TOR Serine-Threonine Kinases - metabolism ; Transfection ; Tumor cell lines ; Tumorigenicity ; Tyrphostins - pharmacology ; Up-Regulation</subject><ispartof>Oncogene, 2013-01, Vol.32 (2), p.209-221</ispartof><rights>Macmillan Publishers Limited 2013</rights><rights>COPYRIGHT 2013 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 10, 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c557t-c4e88162850b81e6c8f8014e2feecc9f1a961b6a0adf8b8a010c35aa18f594533</citedby><cites>FETCH-LOGICAL-c557t-c4e88162850b81e6c8f8014e2feecc9f1a961b6a0adf8b8a010c35aa18f594533</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2012.37$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2012.37$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22370645$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jung, M-J</creatorcontrib><creatorcontrib>Rho, J-K</creatorcontrib><creatorcontrib>Kim, Y-M</creatorcontrib><creatorcontrib>Jung, J E</creatorcontrib><creatorcontrib>Jin, Y B</creatorcontrib><creatorcontrib>Ko, Y-G</creatorcontrib><creatorcontrib>Lee, J-S</creatorcontrib><creatorcontrib>Lee, S-J</creatorcontrib><creatorcontrib>Lee, J C</creatorcontrib><creatorcontrib>Park, M-J</creatorcontrib><title>Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of epithelial–mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity
in vitro
and tumorigenicity
in vivo
. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance
in vitro
and exhibited stronger tumorigenic potential
in vivo
than CXCR4− cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>631/67/1059/2326</subject><subject>631/67/71</subject><subject>631/80/86</subject><subject>692/699/67/1612/1350</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Chemokine CXCL12 - metabolism</subject><subject>CXCR4 protein</subject><subject>Data processing</subject><subject>Development and progression</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Female</subject><subject>Heterocyclic Compounds - pharmacology</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Lung cancer</subject><subject>Lung cancer, Non-small cell</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Mice, SCID</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - physiology</subject><subject>Non-small cell lung carcinoma</subject><subject>Oncology</subject><subject>original-article</subject><subject>Phosphatidylinositol 3-Kinase - metabolism</subject><subject>Phosphoinositide-3 Kinase Inhibitors</subject><subject>Phosphorylation</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>PTEN Phosphohydrolase - genetics</subject><subject>PTEN Phosphohydrolase - metabolism</subject><subject>PTEN protein</subject><subject>Pyridines - pharmacology</subject><subject>Receptors, CXCR4 - antagonists & inhibitors</subject><subject>Receptors, CXCR4 - genetics</subject><subject>Receptors, CXCR4 - metabolism</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering</subject><subject>SDF-1 protein</subject><subject>Secretion</subject><subject>Signal Transduction</subject><subject>siRNA</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor - antagonists & inhibitors</subject><subject>STAT3 Transcription Factor - genetics</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Stem cells</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Transfection</subject><subject>Tumor cell lines</subject><subject>Tumorigenicity</subject><subject>Tyrphostins - pharmacology</subject><subject>Up-Regulation</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkkuLFDEUhYMoTju6ci8BN4JWm0cllVoOjS8YEMQBdyGdvikyVCVtUlkM-ONN7PHJLCSQwM13Djc3B6GnlGwp4ep1DHbLCGVbPtxDG9oPshNi7O-jDRkF6UbG2Rl6lPM1IWQYCXuIzhjjA5G92KBvV8cEU5nN6mPA0eHdl92nHvuMXQm2Fc0832CbivVmxi4mvBgfVggmWGiCvMISIGfsAz6kMnUJss-rCSsOMXR5qQbYQt3mEiZsmy79KOTH6IEzc4Ynt-c5unr75vPufXf58d2H3cVlZ4UY1s72oBSVTAmyVxSkVU4R2gNzANaOjppR0r00xByc2itDKLFcGEOVq3MQnJ-jFyffY4pfC-RVLz63DkyAWLKmbOC8zkkO_4NWWDKpKvr8H_Q6llTn1Sip6KCYIL-pycygfXBxTcY2U33BqWj_wPtKbe-g6jrA4m0M4Hyt_yV4eRLYFHNO4PQx-cWkG02JbrHQNRa6xULz9qpnt62W_QKHX-zPHFTg1QnI9SpMkP54yx1-3wGbmcAn</recordid><startdate>20130110</startdate><enddate>20130110</enddate><creator>Jung, M-J</creator><creator>Rho, J-K</creator><creator>Kim, Y-M</creator><creator>Jung, J E</creator><creator>Jin, Y B</creator><creator>Ko, Y-G</creator><creator>Lee, J-S</creator><creator>Lee, S-J</creator><creator>Lee, J C</creator><creator>Park, M-J</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20130110</creationdate><title>Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells</title><author>Jung, M-J ; Rho, J-K ; Kim, Y-M ; Jung, J E ; Jin, Y B ; Ko, Y-G ; Lee, J-S ; Lee, S-J ; Lee, J C ; Park, M-J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c557t-c4e88162850b81e6c8f8014e2feecc9f1a961b6a0adf8b8a010c35aa18f594533</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>631/67/1059/2326</topic><topic>631/67/71</topic><topic>631/80/86</topic><topic>692/699/67/1612/1350</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Cancer</topic><topic>Cancer cells</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - metabolism</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Care and treatment</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Chemokine CXCL12 - metabolism</topic><topic>CXCR4 protein</topic><topic>Data processing</topic><topic>Development and progression</topic><topic>Drug resistance</topic><topic>Drug Resistance, Neoplasm</topic><topic>Female</topic><topic>Heterocyclic Compounds - pharmacology</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Lung cancer</topic><topic>Lung cancer, Non-small cell</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - pathology</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Mice, SCID</topic><topic>Neoplastic Stem Cells - drug effects</topic><topic>Neoplastic Stem Cells - 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metabolism</topic><topic>Transfection</topic><topic>Tumor cell lines</topic><topic>Tumorigenicity</topic><topic>Tyrphostins - pharmacology</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jung, M-J</creatorcontrib><creatorcontrib>Rho, J-K</creatorcontrib><creatorcontrib>Kim, Y-M</creatorcontrib><creatorcontrib>Jung, J E</creatorcontrib><creatorcontrib>Jin, Y B</creatorcontrib><creatorcontrib>Ko, Y-G</creatorcontrib><creatorcontrib>Lee, J-S</creatorcontrib><creatorcontrib>Lee, S-J</creatorcontrib><creatorcontrib>Lee, J C</creatorcontrib><creatorcontrib>Park, M-J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jung, M-J</au><au>Rho, J-K</au><au>Kim, Y-M</au><au>Jung, J E</au><au>Jin, Y B</au><au>Ko, Y-G</au><au>Lee, J-S</au><au>Lee, S-J</au><au>Lee, J C</au><au>Park, M-J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2013-01-10</date><risdate>2013</risdate><volume>32</volume><issue>2</issue><spage>209</spage><epage>221</epage><pages>209-221</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of epithelial–mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity
in vitro
and tumorigenicity
in vivo
. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance
in vitro
and exhibited stronger tumorigenic potential
in vivo
than CXCR4− cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>22370645</pmid><doi>10.1038/onc.2012.37</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Oncogene, 2013-01, Vol.32 (2), p.209-221 |
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| language | eng |
| recordid | cdi_proquest_miscellaneous_1273392367 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | 1-Phosphatidylinositol 3-kinase 631/67/1059/2326 631/67/71 631/80/86 692/699/67/1612/1350 AKT protein Animals Apoptosis Cancer Cancer cells Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Care and treatment Cell Biology Cell Line, Tumor Chemokine CXCL12 - metabolism CXCR4 protein Data processing Development and progression Drug resistance Drug Resistance, Neoplasm Female Heterocyclic Compounds - pharmacology Human Genetics Humans Internal Medicine Lung cancer Lung cancer, Non-small cell Lung Neoplasms - drug therapy Lung Neoplasms - metabolism Lung Neoplasms - pathology Medicine Medicine & Public Health Mice Mice, Nude Mice, SCID Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - physiology Non-small cell lung carcinoma Oncology original-article Phosphatidylinositol 3-Kinase - metabolism Phosphoinositide-3 Kinase Inhibitors Phosphorylation Proto-Oncogene Proteins c-akt - metabolism PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism PTEN protein Pyridines - pharmacology Receptors, CXCR4 - antagonists & inhibitors Receptors, CXCR4 - genetics Receptors, CXCR4 - metabolism RNA Interference RNA, Small Interfering SDF-1 protein Secretion Signal Transduction siRNA Stat3 protein STAT3 Transcription Factor - antagonists & inhibitors STAT3 Transcription Factor - genetics STAT3 Transcription Factor - metabolism Stem cells TOR protein TOR Serine-Threonine Kinases - metabolism Transfection Tumor cell lines Tumorigenicity Tyrphostins - pharmacology Up-Regulation |
| title | Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T04%3A57%3A48IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Upregulation%20of%20CXCR4%20is%20functionally%20crucial%20for%20maintenance%20of%20stemness%20in%20drug-resistant%20non-small%20cell%20lung%20cancer%20cells&rft.jtitle=Oncogene&rft.au=Jung,%20M-J&rft.date=2013-01-10&rft.volume=32&rft.issue=2&rft.spage=209&rft.epage=221&rft.pages=209-221&rft.issn=0950-9232&rft.eissn=1476-5594&rft.coden=ONCNES&rft_id=info:doi/10.1038/onc.2012.37&rft_dat=%3Cgale_proqu%3EA315370634%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1268178250&rft_id=info:pmid/22370645&rft_galeid=A315370634&rfr_iscdi=true |