Inhibition of CK2α down-regulates Hedgehog/Gli signaling leading to a reduction of a stem-like side population in human lung cancer cells
Protein kinase CK2 is frequently elevated in a variety of human cancers. The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance, and its aberrant activation has been indicated in several types of cancer, including lung cancer. In this study, we show that CK2 is positively i...
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| Veröffentlicht in: | PloS one 2012-06, Vol.7 (6), p.e38996 |
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| creator | Zhang, Shulin Wang, Yucheng Mao, Jian-Hua Hsieh, David Kim, Il-Jin Hu, Li-Min Xu, Zhidong Long, Hao Jablons, David M You, Liang |
| description | Protein kinase CK2 is frequently elevated in a variety of human cancers. The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance, and its aberrant activation has been indicated in several types of cancer, including lung cancer. In this study, we show that CK2 is positively involved in Hh/Gli signaling in lung cancer cell lines A549 and H1299. First, we found a correlation between CK2α and Gli1 mRNA levels in 100 primary lung cancer tissues. Down-regulation of Gli1 expression and transcriptional activity were demonstrated after the silencing of CK2α in lung cancer cells. In addition, CK2α siRNA down-regulated the expression of Hh target genes. Furthermore, two small-molecule CK2α inhibitors led to a dose-dependent inhibition of Gli1 expression and transcriptional activity in lung cancer cells. Reversely, forced over-expression of CK2α resulted in an increase both in Gli1 expression and transcriptional activity in A549 cells. Finally, the inhibition of Hh/Gli by CK2α siRNA led to a reduction of a cancer stem cell-like side population that shows higher ABCG2 expression level. Thus, we report that the inhibition of CK2α down-regulates Hh/Gli signaling and subsequently reduces stem-like side population in human lung cancer cells. |
| doi_str_mv | 10.1371/journal.pone.0038996 |
| format | Article |
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The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance, and its aberrant activation has been indicated in several types of cancer, including lung cancer. In this study, we show that CK2 is positively involved in Hh/Gli signaling in lung cancer cell lines A549 and H1299. First, we found a correlation between CK2α and Gli1 mRNA levels in 100 primary lung cancer tissues. Down-regulation of Gli1 expression and transcriptional activity were demonstrated after the silencing of CK2α in lung cancer cells. In addition, CK2α siRNA down-regulated the expression of Hh target genes. Furthermore, two small-molecule CK2α inhibitors led to a dose-dependent inhibition of Gli1 expression and transcriptional activity in lung cancer cells. Reversely, forced over-expression of CK2α resulted in an increase both in Gli1 expression and transcriptional activity in A549 cells. Finally, the inhibition of Hh/Gli by CK2α siRNA led to a reduction of a cancer stem cell-like side population that shows higher ABCG2 expression level. Thus, we report that the inhibition of CK2α down-regulates Hh/Gli signaling and subsequently reduces stem-like side population in human lung cancer cells.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0038996</identifier><identifier>PMID: 22768056</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aberration ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters - metabolism ; BASIC BIOLOGICAL SCIENCES ; Biology ; Cancer ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - pathology ; Casein kinase II ; Casein Kinase II - antagonists & inhibitors ; Casein Kinase II - metabolism ; Cell Count ; Cell growth ; Cell Line, Tumor ; Down-Regulation - drug effects ; Down-Regulation - genetics ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Knockdown Techniques ; Gene Silencing - drug effects ; Genes ; Hedgehog protein ; hedgehog signaling ; Humans ; Inhibition ; Kinases ; Laboratories ; Leukemia ; lung and intrathoracic tumors ; Lung cancer ; Lung diseases ; Lung Neoplasms - genetics ; Lung Neoplasms - pathology ; Medical prognosis ; Medicine ; Neoplasm Proteins - metabolism ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; non-small cell lung cancer ; Oncology ; Overexpression ; phosphorylation ; Population ; Prostate ; Protein kinase C ; Protein Kinase Inhibitors - pharmacology ; Proteins ; Proteolysis - drug effects ; Reduction ; reverse transcriptase-polymerase chain reaction ; Side-Population Cells - drug effects ; Side-Population Cells - metabolism ; Side-Population Cells - pathology ; Signal transduction ; Signal Transduction - genetics ; Signaling ; siRNA ; small interfering RNA ; Small Molecule Libraries - pharmacology ; Stem cells ; Surgery ; Tissues ; Transcription ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcription, Genetic - drug effects ; Transcriptional Activation - drug effects ; Transcriptional Activation - genetics ; Tumor cell lines ; Up-Regulation - drug effects ; Up-Regulation - genetics ; Zinc Finger Protein GLI1</subject><ispartof>PloS one, 2012-06, Vol.7 (6), p.e38996</ispartof><rights>2012 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Zhang et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c553t-7efdd49338ec28836aeecc687303696fcca47875b6485eeb2b2c57a02e684b13</citedby><cites>FETCH-LOGICAL-c553t-7efdd49338ec28836aeecc687303696fcca47875b6485eeb2b2c57a02e684b13</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/PMC3387212/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387212/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22768056$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/1627526$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Shulin</creatorcontrib><creatorcontrib>Wang, Yucheng</creatorcontrib><creatorcontrib>Mao, Jian-Hua</creatorcontrib><creatorcontrib>Hsieh, David</creatorcontrib><creatorcontrib>Kim, Il-Jin</creatorcontrib><creatorcontrib>Hu, Li-Min</creatorcontrib><creatorcontrib>Xu, Zhidong</creatorcontrib><creatorcontrib>Long, Hao</creatorcontrib><creatorcontrib>Jablons, David M</creatorcontrib><creatorcontrib>You, Liang</creatorcontrib><creatorcontrib>Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)</creatorcontrib><title>Inhibition of CK2α down-regulates Hedgehog/Gli signaling leading to a reduction of a stem-like side population in human lung cancer cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Protein kinase CK2 is frequently elevated in a variety of human cancers. The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance, and its aberrant activation has been indicated in several types of cancer, including lung cancer. In this study, we show that CK2 is positively involved in Hh/Gli signaling in lung cancer cell lines A549 and H1299. First, we found a correlation between CK2α and Gli1 mRNA levels in 100 primary lung cancer tissues. Down-regulation of Gli1 expression and transcriptional activity were demonstrated after the silencing of CK2α in lung cancer cells. In addition, CK2α siRNA down-regulated the expression of Hh target genes. Furthermore, two small-molecule CK2α inhibitors led to a dose-dependent inhibition of Gli1 expression and transcriptional activity in lung cancer cells. Reversely, forced over-expression of CK2α resulted in an increase both in Gli1 expression and transcriptional activity in A549 cells. Finally, the inhibition of Hh/Gli by CK2α siRNA led to a reduction of a cancer stem cell-like side population that shows higher ABCG2 expression level. Thus, we report that the inhibition of CK2α down-regulates Hh/Gli signaling and subsequently reduces stem-like side population in human lung cancer cells.</description><subject>Aberration</subject><subject>ATP Binding Cassette Transporter, Subfamily G, Member 2</subject><subject>ATP-Binding Cassette Transporters - metabolism</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Biology</subject><subject>Cancer</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Casein kinase II</subject><subject>Casein Kinase II - antagonists & inhibitors</subject><subject>Casein Kinase II - metabolism</subject><subject>Cell Count</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Down-Regulation - drug effects</subject><subject>Down-Regulation - genetics</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene Knockdown Techniques</subject><subject>Gene Silencing - 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drug effects</subject><subject>Reduction</subject><subject>reverse transcriptase-polymerase chain reaction</subject><subject>Side-Population Cells - drug effects</subject><subject>Side-Population Cells - metabolism</subject><subject>Side-Population Cells - pathology</subject><subject>Signal transduction</subject><subject>Signal Transduction - genetics</subject><subject>Signaling</subject><subject>siRNA</subject><subject>small interfering RNA</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Stem cells</subject><subject>Surgery</subject><subject>Tissues</subject><subject>Transcription</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription, Genetic - drug effects</subject><subject>Transcriptional Activation - drug effects</subject><subject>Transcriptional Activation - genetics</subject><subject>Tumor cell lines</subject><subject>Up-Regulation - drug effects</subject><subject>Up-Regulation - 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Hybrid</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Shulin</au><au>Wang, Yucheng</au><au>Mao, Jian-Hua</au><au>Hsieh, David</au><au>Kim, Il-Jin</au><au>Hu, Li-Min</au><au>Xu, Zhidong</au><au>Long, Hao</au><au>Jablons, David M</au><au>You, Liang</au><aucorp>Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of CK2α down-regulates Hedgehog/Gli signaling leading to a reduction of a stem-like side population in human lung cancer cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-06-29</date><risdate>2012</risdate><volume>7</volume><issue>6</issue><spage>e38996</spage><pages>e38996-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Protein kinase CK2 is frequently elevated in a variety of human cancers. The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance, and its aberrant activation has been indicated in several types of cancer, including lung cancer. In this study, we show that CK2 is positively involved in Hh/Gli signaling in lung cancer cell lines A549 and H1299. First, we found a correlation between CK2α and Gli1 mRNA levels in 100 primary lung cancer tissues. Down-regulation of Gli1 expression and transcriptional activity were demonstrated after the silencing of CK2α in lung cancer cells. In addition, CK2α siRNA down-regulated the expression of Hh target genes. Furthermore, two small-molecule CK2α inhibitors led to a dose-dependent inhibition of Gli1 expression and transcriptional activity in lung cancer cells. Reversely, forced over-expression of CK2α resulted in an increase both in Gli1 expression and transcriptional activity in A549 cells. Finally, the inhibition of Hh/Gli by CK2α siRNA led to a reduction of a cancer stem cell-like side population that shows higher ABCG2 expression level. Thus, we report that the inhibition of CK2α down-regulates Hh/Gli signaling and subsequently reduces stem-like side population in human lung cancer cells.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22768056</pmid><doi>10.1371/journal.pone.0038996</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-06, Vol.7 (6), p.e38996 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1325028203 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Aberration ATP Binding Cassette Transporter, Subfamily G, Member 2 ATP-Binding Cassette Transporters - metabolism BASIC BIOLOGICAL SCIENCES Biology Cancer Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - pathology Casein kinase II Casein Kinase II - antagonists & inhibitors Casein Kinase II - metabolism Cell Count Cell growth Cell Line, Tumor Down-Regulation - drug effects Down-Regulation - genetics Gene expression Gene Expression Regulation, Neoplastic - drug effects Gene Knockdown Techniques Gene Silencing - drug effects Genes Hedgehog protein hedgehog signaling Humans Inhibition Kinases Laboratories Leukemia lung and intrathoracic tumors Lung cancer Lung diseases Lung Neoplasms - genetics Lung Neoplasms - pathology Medical prognosis Medicine Neoplasm Proteins - metabolism Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology non-small cell lung cancer Oncology Overexpression phosphorylation Population Prostate Protein kinase C Protein Kinase Inhibitors - pharmacology Proteins Proteolysis - drug effects Reduction reverse transcriptase-polymerase chain reaction Side-Population Cells - drug effects Side-Population Cells - metabolism Side-Population Cells - pathology Signal transduction Signal Transduction - genetics Signaling siRNA small interfering RNA Small Molecule Libraries - pharmacology Stem cells Surgery Tissues Transcription Transcription Factors - genetics Transcription Factors - metabolism Transcription, Genetic - drug effects Transcriptional Activation - drug effects Transcriptional Activation - genetics Tumor cell lines Up-Regulation - drug effects Up-Regulation - genetics Zinc Finger Protein GLI1 |
| title | Inhibition of CK2α down-regulates Hedgehog/Gli signaling leading to a reduction of a stem-like side population in human 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=2025-02-07T23%3A32%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Inhibition%20of%20CK2%CE%B1%20down-regulates%20Hedgehog/Gli%20signaling%20leading%20to%20a%20reduction%20of%20a%20stem-like%20side%20population%20in%20human%20lung%20cancer%20cells&rft.jtitle=PloS%20one&rft.au=Zhang,%20Shulin&rft.aucorp=Lawrence%20Berkeley%20National%20Laboratory%20(LBNL),%20Berkeley,%20CA%20(United%20States)&rft.date=2012-06-29&rft.volume=7&rft.issue=6&rft.spage=e38996&rft.pages=e38996-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0038996&rft_dat=%3Cproquest_plos_%3E2940528251%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1325028203&rft_id=info:pmid/22768056&rft_doaj_id=oai_doaj_org_article_e540428714c245059c3c4feaac0279b0&rfr_iscdi=true |