Regulation and novel action of thymidine phosphorylase in non-small cell lung cancer : crosstalk with Nrf2 and HO-1

2014
journal article
article
dc.abstract.enProangiogenic enzyme thymidine phosphorylase (TP) is a promising target for anticancer therapy, yet its action in non-small cell lung carcinoma (NSCLC) is not fully understood. To elucidate its role in NSCLC tumor growth, NCI-H292 lung mucoepidermoid carcinoma cells and endothelial cells were engineered to overexpress TP by viral vector transduction. NSCLC cells with altered expression of transcription factor Nrf2 or its target gene heme oxygenase-1 (HO-1) were used to study the regulation of TP and the findings from pre-clinical models were related to gene expression data from clinical NSCLC specimens. Overexpression of Nrf2 or HO-1 resulted in upregulation of TP in NCI-H292 cells, an effect mimicked by treatment with an antioxidant N-acetylcysteine and partially reversed by HO-1 knockdown. Overexpression of TP attenuated cell proliferation and migration in vitro, but simultaneously enhanced angiogenic potential of cancer cells supplemented with thymidine. The latter was also observed for SK-MES-1 squamous cell carcinoma and NCI-H460 large cell carcinoma cells. TP-overexpressing NCI-H292 tumors in vivo exhibited better oxygenation and higher expression of IL-8, IL-1β and IL-6. TP overexpression in endothelial cells augmented their angiogenic properties which was associated with enhanced generation of HO-1 and VEGF. Correlation of TP with the expression of HO-1 and inflammatory cytokines was confirmed in clinical samples of NSCLC. Altogether, the increased expression of IL-1β and IL-6 together with proangiogenic effects of TP-expressing NSCLC on endothelium can contribute to tumor growth, implying TP as a target for antiangiogenesis in NSCLC.pl
dc.affiliationWydział Biochemii, Biofizyki i Biotechnologii : Zakład Biotechnologii Medycznejpl
dc.affiliationWydział Nauk o Zdrowiu : Instytut Fizjoterapiipl
dc.cm.id66077
dc.contributor.authorTertil, Magdalena - 104002 pl
dc.contributor.authorSkrzypek, Klaudia - 103991 pl
dc.contributor.authorFlorczyk-Soluch, Urszula - 104023 pl
dc.contributor.authorWeglarczyk, Kazimierzpl
dc.contributor.authorWaś, Halina - 174086 pl
dc.contributor.authorCollet, Guillaumepl
dc.contributor.authorGuichard, Alanpl
dc.contributor.authorGil, Tomasz - 200745 pl
dc.contributor.authorKużdżał, Jarosław - 199984 pl
dc.contributor.authorJózkowicz, Alicja - 128541 pl
dc.contributor.authorKieda, Claudinepl
dc.contributor.authorPichon, Chantalpl
dc.contributor.authorDulak, Józef - 127818 pl
dc.date.accessioned2015-05-18T10:36:07Z
dc.date.available2015-05-18T10:36:07Z
dc.date.issued2014pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.additionalUrszula Florczyk-Soluch podpisana: Urszula Florczykpl
dc.description.number5pl
dc.description.points40pl
dc.description.versionostateczna wersja wydawcy
dc.description.volume9pl
dc.identifier.articleide97070pl
dc.identifier.doi10.1371/journal.pone.0097070pl
dc.identifier.eissn1932-6203pl
dc.identifier.projectROD UJ / Ppl
dc.identifier.urihttp://ruj.uj.edu.pl/xmlui/handle/item/7288
dc.languageengpl
dc.language.containerengpl
dc.rightsUdzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa*
dc.rights.licenceCC-BY
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/legalcode.pl*
dc.share.typeotwarte czasopismo
dc.subtypeArticlepl
dc.titleRegulation and novel action of thymidine phosphorylase in non-small cell lung cancer : crosstalk with Nrf2 and HO-1pl
dc.title.journalPLoS ONEpl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.enpl
Proangiogenic enzyme thymidine phosphorylase (TP) is a promising target for anticancer therapy, yet its action in non-small cell lung carcinoma (NSCLC) is not fully understood. To elucidate its role in NSCLC tumor growth, NCI-H292 lung mucoepidermoid carcinoma cells and endothelial cells were engineered to overexpress TP by viral vector transduction. NSCLC cells with altered expression of transcription factor Nrf2 or its target gene heme oxygenase-1 (HO-1) were used to study the regulation of TP and the findings from pre-clinical models were related to gene expression data from clinical NSCLC specimens. Overexpression of Nrf2 or HO-1 resulted in upregulation of TP in NCI-H292 cells, an effect mimicked by treatment with an antioxidant N-acetylcysteine and partially reversed by HO-1 knockdown. Overexpression of TP attenuated cell proliferation and migration in vitro, but simultaneously enhanced angiogenic potential of cancer cells supplemented with thymidine. The latter was also observed for SK-MES-1 squamous cell carcinoma and NCI-H460 large cell carcinoma cells. TP-overexpressing NCI-H292 tumors in vivo exhibited better oxygenation and higher expression of IL-8, IL-1β and IL-6. TP overexpression in endothelial cells augmented their angiogenic properties which was associated with enhanced generation of HO-1 and VEGF. Correlation of TP with the expression of HO-1 and inflammatory cytokines was confirmed in clinical samples of NSCLC. Altogether, the increased expression of IL-1β and IL-6 together with proangiogenic effects of TP-expressing NSCLC on endothelium can contribute to tumor growth, implying TP as a target for antiangiogenesis in NSCLC.
dc.affiliationpl
Wydział Biochemii, Biofizyki i Biotechnologii : Zakład Biotechnologii Medycznej
dc.affiliationpl
Wydział Nauk o Zdrowiu : Instytut Fizjoterapii
dc.cm.id
66077
dc.contributor.authorpl
Tertil, Magdalena - 104002
dc.contributor.authorpl
Skrzypek, Klaudia - 103991
dc.contributor.authorpl
Florczyk-Soluch, Urszula - 104023
dc.contributor.authorpl
Weglarczyk, Kazimierz
dc.contributor.authorpl
Waś, Halina - 174086
dc.contributor.authorpl
Collet, Guillaume
dc.contributor.authorpl
Guichard, Alan
dc.contributor.authorpl
Gil, Tomasz - 200745
dc.contributor.authorpl
Kużdżał, Jarosław - 199984
dc.contributor.authorpl
Józkowicz, Alicja - 128541
dc.contributor.authorpl
Kieda, Claudine
dc.contributor.authorpl
Pichon, Chantal
dc.contributor.authorpl
Dulak, Józef - 127818
dc.date.accessioned
2015-05-18T10:36:07Z
dc.date.available
2015-05-18T10:36:07Z
dc.date.issuedpl
2014
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.additionalpl
Urszula Florczyk-Soluch podpisana: Urszula Florczyk
dc.description.numberpl
5
dc.description.pointspl
40
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
9
dc.identifier.articleidpl
e97070
dc.identifier.doipl
10.1371/journal.pone.0097070
dc.identifier.eissnpl
1932-6203
dc.identifier.projectpl
ROD UJ / P
dc.identifier.uri
http://ruj.uj.edu.pl/xmlui/handle/item/7288
dc.languagepl
eng
dc.language.containerpl
eng
dc.rights*
Udzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa
dc.rights.licence
CC-BY
dc.rights.uri*
http://creativecommons.org/licenses/by/4.0/legalcode.pl
dc.share.type
otwarte czasopismo
dc.subtypepl
Article
dc.titlepl
Regulation and novel action of thymidine phosphorylase in non-small cell lung cancer : crosstalk with Nrf2 and HO-1
dc.title.journalpl
PLoS ONE
dc.typepl
JournalArticle
dspace.entity.type
Publication

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