title: Regulation and novel action of thymidine phosphorylase in non-small cell lung cancer: crosstalk with Nrf2 and HO-1.
abstract: 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.
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Centre de Biophysique Moleculaire, CNRS UPR4301, Orléans, France; Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Tertil
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Centre de Biophysique Moleculaire, CNRS UPR4301, Orléans, France.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Skrzypek
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Urszula
authors.initials: U
authors.lastname: Florczyk
authors.affiliation: Centre de Biophysique Moleculaire, CNRS UPR4301, Orléans, France.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Weglarczyk
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Halina
authors.initials: H
authors.lastname: Was
authors.affiliation: Centre de Biophysique Moleculaire, CNRS UPR4301, Orléans, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Collet
authors.affiliation: Centre de Biophysique Moleculaire, CNRS UPR4301, Orléans, France.
authors.forename: Alan
authors.initials: A
authors.lastname: Guichard
authors.affiliation: Department of Thoracic Surgery, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gil
authors.affiliation: Department of Thoracic Surgery, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Kuzdzal
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Jozkowicz
authors.affiliation: Centre de Biophysique Moleculaire, CNRS UPR4301, Orléans, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Kieda
authors.affiliation: Centre de Biophysique Moleculaire, CNRS UPR4301, Orléans, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Pichon
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D013939:Thymidine Phosphorylase / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D013939:Thymidine Phosphorylase