Decoy molecules based on PNA-DNA chimeras and targeting Sp1 transcription factors inhibit the activity of urokinase-type plasminogen activator receptor (uPAR) promoter
Decoy molecules based on PNA-DNA chimeras and targeting Sp1 transcription factors inhibit the activity of urokinase-type plasminogen activator receptor (uPAR) promoter(438 views) Borgatti M, Boyd DD, Lampronti I, Bianchi N, Fabbri E, Saviano M, Romanelli A, Pedone C, Gambari R
Oncology Research (ISSN: 0965-0407), 2005; 15(7-8): 373-383.
Department of Biochemistry and Molecular Biology, Section of Molecular Biology, Ferrara University, Ferrara, Italy
Department of Cancer Biology, M.D. Anderson Cancer Center, University of Texas, Houston, TX, United States
Institute of Biostructures and Bioimages, CNR, Napoli, Italy
Department of Biological Sciences, University of Naples Frederico II, Naples, Italy
Biotechnology Centre, Ferrara University, Ferrara, Italy
References: De Bock, C.E., Wang, Y., Clinical significance of urokinase-type plasminogen activator receptor (uPAR) expression in cancer (2004) Med. Res. Rev., 24, pp. 13-3
Andreasen, P.A., Egelund, R., Petersen, H.H., The plasminogen activation system in tumor growth, invasion, and metastasis (2000) Cell. Mol. Life Sci., 57, pp. 25-40
Moriyama, T., Kataoka, H., Hamasuna, R., Yoshida, E., Sameshima, T., Iseda, T., Yokogami, K., Wakisaka, S., Simultaneous up-regulation of urokinase-type plasminogen activator (uPA) and uPA receptor by hepatocyte growth factor/scatter factor in human glioma cells (1999) Clin. Exp. Metastasis, 17, pp. 873-879
Okusa, Y., Ichikura, T., Mochizuki, H., Shinomiya, N., Urokinase type plasminogen activator and its receptor regulate the invasive potential of gastric cancer cell lines (2000) Int. J. Oncol., 17, pp. 1001-1005
Hollas, W., Soravia, E., Mazar, A., Henkin, J., Blasi, F., Boyd, D., Decreased urokinase receptor expression by overexpression of the plasminogen activator in a colon cancer cell line (1992) Biochem. J., 285, pp. 629-634
Bruckner, A., Fielderman, A.E., Kirchheimer, J.C., Binder, B.R., Remold, H.G., Endogenous receptor-bound urokinase mediates tissue invasion of the human lung carcinoma cell lines A549 and Calu-1 (1992) Cancer Res., 52, pp. 3043-3047
Crowley, C.W., Cohen, R.L., Lucas, B.K., Liu, G., Shuman, M.A., Levinson, A.D., Prevention of metastasis by inhibition of the urokinase receptor (1993) Proc. Natl. Acad. Sci. USA, 90, pp. 5021-5025
Pedersen, H., Brinner, N., Francio, D., Osterlind, K., Rìnne, E., Hansen, H.H., Dano, K., Grìndahl-Hansen, J., Prognostic impact of urokinase, urokinase receptor and type 1 plasminogen activator inhibitor in squamous- and large-cell lung-cancer tissue (1994) Cancer Res., 54, pp. 4671-4675
Stahl, A., Mueller, B.M., Binding of urokinase to its receptor promotes migration and invasion of human melanoma cells in vitro (1994) Cancer Res., 54, pp. 3066-3067
Kobayashi, H., Gotoh, J., Fujie, M., Shinohara, H., Moniwa, N., Terao, T., Inhibition of metastasis of Lewis lung carcinoma by a synthetic peptide within growth factor-like domain of urokinase in the experimental and spontaneous metastasis model (1994) Int. J. Cancer, 57, pp. 727-733
Kaneko, T., Konno, H., Baba, M., Tanaka, T., Nakamura, S., Urokinase-type plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer (2003) Cancer Sci., 94, pp. 43-49
Nishimura, K., Matsumiya, K., Miura, H., Tsujimura, A., Nonomura, N., Matsumoto, K., Nakamura, T., Okuyama, A., Effects of hepatocyte growth factor on urokinase-type plasminogen activator (uPA) and uPA receptor in DU145 prostate cancer cells (2003) Int. J. Androl., 26, pp. 175-179
Vallera, D.A., Li, C., Jin, N., Panoskaltsis-Mortari, A., Hall, W.A., Targeting urokinase-type plasminogen activator receptor on human glioblastoma tumors with diphtheria toxin fusion protein DTAT (2002) J. Natl. Cancer Inst., 94, pp. 597-606
Rabbani, S.A., Gladu, J., Urokinase receptor antibody can reduce tumor volume and detect the presence of occult tumor metastases in vivo (2002) Cancer Res., 62, pp. 2390-2397
Mohanam, S., Jasti, S.L., Kondraganti, S.R., Chandrasekar, N., Kin, Y., Fuller, G.N., Lakka, S.S., Rao, J.S., Stable transfection of urokinase-type plasminogen activator antisense construct modulates invasion of human glioblastoma cells (2001) Clin. Cancer Res., 7, pp. 2519-2526
Soravia, E., Grebe, A., De Luca, P., Helin, K., Suh, T.T., Degen, J.L., Blasi, F., A conserved TATA-less proximal promoter drives basal transcription from the urokinase-type plasminogen activator receptor gene (1995) Blood, 86, pp. 624-635
Lengyel, E., Wang, H., Stepp, E., Juarez, J., Wang, Y., Doe, W., Pfarr, C.M., Boyd, D., Requirement of an upstream AP-1 motif for the constitutive and phorbol ester-inducible expression of the urokinase-type plasminogen activator receptor gene (1996) J. Biol. Chem., 271, pp. 23176-23184
Dang, J., Boyd, D., Wang, H., Allgayer, H., Doe, W.F., Wang, Y., A region between -141 and -61 bp containing a proximal AP-1 is essential for constitutive expression of urokinase-type plasminogen activator receptor (1999) Eur. J. Biochem., 264, pp. 92-99
Allgayer, H., Wang, H., Gallick, G.E., Crabtree, A., Mazar, A., Jones, T., Kraker, A.J., Boyd, D.D., Transcriptional induction of the urokinase receptor gene by a constitutively active Src. Requirement of an upstream motif (-152/-135) bound with Sp1 (1999) J. Biol. Chem., 274, pp. 18428-18437
Gambari, R., New trends in the development of transcription factor decoy (TFD) pharmacotherapy (2004) Curr. Drug Targets, 5, pp. 419-430
Piva, R., Gambari, R., Transcription factor decoy (TFD) in breast cancer research and treatment (2002) Technol. Cancer Res. Treat., 1, pp. 405-416
Morishita, R., Perspective in progress of cardiovascular gene therapy (2004) J. Pharmacol. Sci., 95, pp. 1-8
Morishita, R., Sugimoto, T., Aoki, M., Kida, I., Tomita, N., Moriguchi, A., Maeda, K., Ogihara, T., In vivo transfection of cis element "decoy" against nuclear factor-kappaB binding site prevents myocardial infarction (1997) Nat. Med., 3, pp. 894-899
Tomita, N., Kim, J.Y., Gibbons, G.H., Zhang, L., Kaneda, Y., Stahl, R.A., Ogborn, M., Dzau, V.J., Gene therapy with an E2F transcription factor decoy inhibits cell cycle progression in rat anti-Thy 1 glomerulonephritis (2004) Int. J. Mol. Med., 13, pp. 629-636
Nielsen, P.E., Egholm, M., Berg, R.H., Buchardt, O., Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide (1991) Science, 254, pp. 1497-1500
Egholm, M., Buchardt, O., Christensen, L., Behrens, C., Freier, S.M., Driver, D.A., Berg, R.H., Nielsen, P.E., PNA hybridizes to complementary oligonucleotides obeying the Watson-Crick hydrogen-bonding rules (1993) Nature, 365, pp. 566-568
Gambari, R., Peptide-nucleic acids (PNAs): A tool for the development of gene expression modifiers (2001) Curr. Pharm. Des., 7, pp. 1839-1862
Saviano, M., Romanelli, A., Bucci, E., Pedone, C., Mischiati, C., Bianchi, N., Feriotto, G., Gambari, R., Computational procedures to explain the different biological activity of DNA/DNA, DNA/PNA and PNA/PNA hybrid molecules mimicking NF-kappaB binding sites (2000) J. Biomol. Struct. Dyn., 18, pp. 353-362
Demidov, V.V., Potaman, V.N., Frank-Kamenetskii, M.D., Egholm, M., Buchard, O., Sonnichsen, S.H., Nielsen, P.E., Stability of peptide nucleic acids in human serum and cellular extracts (1994) Biochem. Pharmacol., 48, pp. 1310-1313
Betts, L., Josey, J.A., Veal, J.M., Jordan, S.R., A nucleic acid triple helix formed by a peptide nucleic acid-DNA complex (1995) Science, 270, pp. 1838-1841
Larsen, H.J., Nielsen, P.E., Transcription-mediated binding of peptide nucleic acid (PNA) to double-stranded DNA: Sequence-specific suicide transcription (1996) Nucleic Acids Res, 24, pp. 458-463
Gambari, R., Biological activity and delivery of peptide nucleic acids (PNA) -DNA chimeras for transcription factor decoy (TFD) pharmacotherapy (2004) Curr. Med. Chem., 11, pp. 1253-1263
Romanelli, A., Pedone, C., Saviano, M., Bianchi, N., Borgatti, M., Mischiati, C., Gambari, R., Molecular interactions with nuclear factor kappaB (NF-kappaB) transcription factors of a PNA-DNA chimera mimicking NF-kappaB binding sites (2001) Eur. J. Biochem., 268, pp. 6066-6075
Borgatti, M., Breda, L., Cortesi, R., Nastruzzi, C., Romanelli, A., Saviano, M., Bianchi, N., Gambari, R., Cationic liposomes as delivery systems for double-stranded PNA-DNA chimeras exhibiting decoy activity against NF-kappaB transcription factors (2002) Biochem. Pharmacol., 64, pp. 609-616
Borgatti, M., Lampronti, I., Romanelli, A., Pedon, C., Saviano, M., Bianchi, N., Mischiati, C., Gambari, R., Transcription factor decoy molecules based on a peptide nucleic acid (PNA) -DNA chimera mimicking Sp1 binding sites (2003) J. Biol. Chem., 278, pp. 7500-7509
Borgatti, M., Romanelli, A., Saviano, M., Pedone, C., Lampronti, I., Breda, L., Nastruzzi, C., Gambari, R., Resistance of decoy PNA-DNA chimeras to enzymatic degradation in cellular extracts and serum (2003) Oncol. Res., 13, pp. 279-287
Dignam, J.D., Lebovitz, R.M., Roeder, R.G., Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei (1983) Nucleic Acids Res., 11, pp. 1475-1489
Feriotto, G., Finotti, A., Volpe, P., Treves, S., Ferrari, S., Angelelli, C., Zorzato, F., Gambari, R., MEF-2 activates promoter sequences of the human AβH-J-J locus, encoding aspartyl-β-hydroxylase, junctin and junctate (2005) Mol. Cell. Biol., 25, pp. 3261-3275
Hall, J.M., McDonnel, D.P., Korach, K.S., Allosteric regulation of estrogen receptor structure, function and co-activator recruitment by different estrogen response elements (2002) Mol. Endocrinol., 16, pp. 469-486
Cohn, M.A., Hjelmso, I., Wu, L.C., Guldberg, P., Lukanidin, E.M., Tulchinsky, E.M., Characterization of Sp1, AP-1, CBF and KRC binding sites and minisatellite DNA as functional elements of the metastasis-associated mts1/S100A4 gene intronic enhancer (2001) Nucleic Acids Res., 29, pp. 3335-3346
Lang, J.C., Whitelaw, B., Talbot, S., Wilkie, N.M., Transcriptional regulation of the human c-myc gene (1988) Br. J. Cancer, 9, pp. 62-66
Black, A.R., Black, J.D., Azizkhan-Clifford, J., Sp1 and kruppel-like factor family of transcription factors in cell growth regulation and cancer (2001) J. Cell. Physiol., 188, pp. 143-160
Chae, Y.M., Park, K.K., Magae, J., Lee, I.S., Kim, C.H., Kim, H.C., Hong, S., Chang, Y.C., Sp1-decoy oligodeoxynucleotide inhibits high glucose-induced mesangial cell proliferation (2004) Biochem. Biophys. Res. Commun., 319, pp. 50-55
Novak, E.M., Metzger, M., Chammas, R., Da Costa, M., Dantas, K., Manabe, C., Pires, J., Bydlowski, S.P., Downregulation of TNF-alpha and VEGF expression by Sp1 decoy oligodeoxynucleotides in mouse melanoma tumor (2003) Gene Ther., 10, pp. 1992-1997
Ishibashi, H., Nakagawa, K., Onimaru, M., Castellanous, E.J., Kaneda, Y., Nakashima, Y., Shirasuna, K., Sueishi, K., Sp1 decoy transfected to carcinoma cells suppresses the expression of vascular endothelial growth factor, transforming growth factor beta1, and tissue factor and also cell growth and invasion activities (2000) Cancer Res., 60, pp. 6531-6536
Mischiati, C., Sereni, A., Finotti, A., Breda, L., Cortesi, R., Nastruzzi, C., Romanelli, A., Gambari, R., Complexation to cationic microspheres of double-stranded peptide nucleic acid-DNA chimeras exhibiting decoy activity (2004) J. Biomed. Sci., 11, pp. 697-704
Nair, R.R., Wang, H., Fokt, I., Priebe, W., Boyd, D.D., A bisanthracycline (WP631) represses u-PAR gene expression and cell migration by interfering with transcription factor binding to a chromatin-accessible -148/-124 promoter region (2005) Oncol. Res., 15, pp. 265-279
Shetty, S., Idell, S., Urokinase induces expression of its own receptor in Beas2B lung epithelial cells (2001) J. Biol. Chem., 276, pp. 24549-24556
Park, I.K., Lyu, M.A., Yeo, S.J., Han, T.H., Kook, Y.H., Sp1 mediates constitutive and transforming growth factor beta-inducible expression of urokinase type plasminogen activator receptor gene in human monocyte-like U937 cells (2000) Biochim. Biophys. Acta, 1490, pp. 302-310
Hata, Y., Duh, E., Zhang, K., Robinson, G.S., Aiello, L.P., Transcription factors Sp1 and Sp3 alter vascular endothelial growth factor receptor expression through a novel recognition sequence (1998) J. Biol. Chem., 273, pp. 19294-19303
Decoy molecules based on PNA-DNA chimeras and targeting Sp1 transcription factors inhibit the activity of urokinase-type plasminogen activator receptor (uPAR) promoter
The expression levels of urokinase-type plasminogen activator receptor (uPAR) are strongly correlated with metastatic potential in human cancer cell lines of melanoma, breast, lung, and colon. Therefore, targeting of uPAR could have practical implications in the treatment of neoplastic diseases. Because the expression of uPAR is regulated at the level of transcription in part by Sp1, we designed and tested transcription factors decoy molecules targeting Sp1 with the aim of inhibiting uPAR gene expression. The main objective of the present study was to determine whether decoy molecules based on peptide nucleic acids (PNA)-DNA chimeras mimicking Sp1 binding sites might be proposed as useful reagents to alter expression of Sp1-regulated genes involved in tumor invasion and metastasis. The results obtained firmly indicate that Sp1 binding molecules based on PNA-DNA-PNA chimeras are powerful decoys, as they efficiently inhibit the interactions between Sp1 and the uPAR promoter elements. Experiments performed on hepatoma HepG2 cells transfected with a plasmid containing the firefly luciferase gene reporter under the control of the human uPAR promoter demonstrate that PNA-DNA-PNA-based decoy molecules are potent inhibitors of the transcriptional activity of the uPAR promoter. Our results suggest that these molecules warrant attention for the design of novel antimetastatic drugs.
Decoy molecules based on PNA-DNA chimeras and targeting Sp1 transcription factors inhibit the activity of urokinase-type plasminogen activator receptor (uPAR) promoter
Decoy molecules based on PNA-DNA chimeras and targeting Sp1 transcription factors inhibit the activity of urokinase-type plasminogen activator receptor (uPAR) promoter