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Journal of Cancer Research and Clinical Oncology

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Open Access 01-05-2014 | Review

Cell-surface nucleolin acts as a central mediator for carcinogenic, anti-carcinogenic, and disease-related ligands

Authors: Hirota Fujiki, Tatsuro Watanabe, Masami Suganuma

Published in: Journal of Cancer Research and Clinical Oncology | Issue 5/2014

Abstract

Purpose

Cell-surface nucleolin in human gastric cancer cell lines is a receptor for TNF-α-inducing protein (Tipα) of Helicobacter pylori. The binding complex of nucleolin and Tipα is internalized into the cells and then induces tumor progression of human gastric cancer. Surface nucleolin is also a receptor of human immunodeficiency virus-1, and the anti-HIV pseudopeptide (HB-19) showed anti-carcinogenic activity in vivo. Surface nucleolin has dual functions depending on the ligands: In order to understand the mechanisms of surface nucleolin, it is necessary to review surface nucleolin and its relation to carcinogenic ligands and anti-carcinogenic ligands. Other ligands can be grouped among disease-related ligands, which is an important new topic for the prevention of various ailments.

Results and discussion

This paper mainly deals with two ligands of surface nucleolin, Tipα and pseudopeptide HB-19. The binding complex of nucleolin and Tipα induces expression of TNF-α and chemokine genes and activates NF-κB in gastric cancer cells of humans and mice. However, when human gastric cancer cell line MKN-1 was transfected with nucleolin-targeted siRNA, the result was inhibition of cell migration and elongation induced by Tipα. The amount of surface nucleolin was reduced in membrane fraction of the nucleolin knockdown MKN-1 cells, but the amount of nucleolin in the cytosol or nuclear fractions of the cells did not change. The results indicate that surface nucleolin acts as a carcinogenic mediator for Tipα of H. pylori. In contrast, both the viral external envelop glycoprotein gp120 of HIV and the anti-HIV pseudopeptide HB-19 bind to surface nucleolin. Through this binding, treatment with HB-19 inhibited tumor development in human breast cancer cell line MDA-MB-231 and rhabdoid tumor cell line derived from Wilms’s tumor in xenograft nude mouse models. The results show that surface nucleolin acts as an anti-carcinogenic mediator for HB-19.

Conclusion

Based on these discrete functions of surface nucleolin, the binding complex of carcinogenic ligands and surface nucleolin seems to be competing with that of anti-carcinogenic ligands and surface nucleolin. Moreover, carcinogenic ligands derived from endogenous sources play a significant role in human cancer development, and the interaction of surface nucleolin with disease-related ligands will be a new research subject for the prevention and treatment of various ailments.

Allain FH, Bouvet P, Dieckmann T, Feigon J (2000) Molecular basis of sequence-specific recognition of pre-ribosomal RNA by nucleolin. EMBO J 19(24):6870–6881CrossRefPubMedPubMedCentral

Amsterdam A, Sadler KC, Lai K, Farrington S, Bronson RT, Lees JA, Hopkins N (2004) Many ribosomal protein genes are cancer genes in zebrafish. PLoS Biol 2(5):E139CrossRefPubMedPubMedCentral

Arumugam S, Miller MC, Maliekal J, Bates PJ, Trent JO, Lane AN (2010) Solution structure of the RBD1,2 domains from human nucleolin. J Biomol NMR 47(1):79–83CrossRefPubMed

Barel M, Hovanessian AG, Meibom K, Briand JP, Dupuis M, Charbit A (2008) A novel receptor—ligand pathway for entry of Francisella tularensis in monocyte-like THP-1 cells: interaction between surface nucleolin and bacterial elongation factor Tu. BMC Microbiol 8:145CrossRefPubMedPubMedCentral

Belenguer P, Baldin V, Mathieu C, Prats H, Bensaid M, Bouche G, Amalric F (1989) Protein kinase NII and the regulation of rDNA transcription in mammalian cells. Nucleic Acids Res 17(16):6625–6636CrossRefPubMedPubMedCentral

Birchenall-Roberts MC, Fu T, Kim SG, Huang YK, Dambach M, Resau JH, Ruscetti FW (2006) K-Ras4B proteins are expressed in the nucleolus: interaction with nucleolin. Biochem Biophys Res Commun 348(2):540–549CrossRefPubMed

Bourguignon LY (2008) Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin Cancer Biol 18(4):251–259CrossRefPubMedPubMedCentral

Bugler B, Caizergues-Ferrer M, Bouche G, Bourbon H, Amalric F (1982) Detection and localization of a class of proteins immunologically related to a 100-kDa nucleolar protein. Eur J Biochem 128(2–3):475–480PubMed

Callebaut C, Blanco J, Benkirane N, Krust B, Jacotot E, Guichard G, Seddiki N, Svab J, Dam E, Muller S, Briand JP, Hovanessian AG (1998) Identification of V3 loop-binding proteins as potential receptors implicated in the binding of HIV particles to CD4(+) cells. J Biol Chem 273(34):21988–21997CrossRefPubMed

Carpentier M, Morelle W, Coddeville B, Pons A, Masson M, Mazurier J, Legrand D (2005) Nucleolin undergoes partial N- and O-glycosylations in the extranuclear cell compartment. Biochemistry (Mosc) 44(15):5804–5815CrossRef

Christian S, Pilch J, Akerman ME, Porkka K, Laakkonen P, Ruoslahti E (2003) Nucleolin expressed at the cell surface is a marker of endothelial cells in angiogenic blood vessels. J Cell Biol 163(4):871–878CrossRefPubMedPubMedCentral

de Verdugo UR, Selinka HC, Huber M, Kramer B, Kellermann J, Hofschneider PH, Kandolf R (1995) Characterization of a 100-kilodalton binding protein for the six serotypes of coxsackie B viruses. J Virol 69(11):6751–6757PubMedPubMedCentral

Destouches D, El Khoury D, Hamma-Kourbali Y, Krust B, Albanese P, Katsoris P, Guichard G, Briand JP, Courty J, Hovanessian AG (2008) Suppression of tumor growth and angiogenesis by a specific antagonist of the cell-surface expressed nucleolin. PLoS One 3(6):e2518CrossRefPubMedPubMedCentral

Destouches D, Page N, Hamma-Kourbali Y, Machi V, Chaloin O, Frechault S, Birmpas C, Katsoris P, Beyrath J, Albanese P, Maurer M, Carpentier G, Strub JM, Van Dorsselaer A, Muller S, Bagnard D, Briand JP, Courty J (2011) A simple approach to cancer therapy afforded by multivalent pseudopeptides that target cell-surface nucleoproteins. Cancer Res 71(9):3296–3305CrossRefPubMed

Di Segni A, Farin K, Pinkas-Kramarski R (2008) Identification of nucleolin as new ErbB receptors-interacting protein. PLoS One 3(6):e2310CrossRefPubMedPubMedCentral

El Khoury D, Destouches D, Lengagne R, Krust B, Hamma-Kourbali Y, Garcette M, Niro S, Kato M, Briand JP, Courty J, Hovanessian AG, Prévost-Blondel A (2010) Targeting surface nucleolin with a multivalent pseudopeptide delays development of spontaneous melanoma in RET transgenic mice. BMC Cancer 10:325CrossRefPubMedPubMedCentral

Fujiki H (2014) Gist of Dr. Katsusaburo Yamagiwa’s papers entitled “Experimental study on the pathogenesis of epithelial tumors” (I to VI reports). Cancer Sci. doi:10.1111/cas.12333 PubMedPubMedCentral

Fujiki H, Suganuma M (1993) Tumor promotion by inhibitors of protein phosphatases 1 and 2A: the okadaic acid class of compounds. Adv Cancer Res 61:143–194CrossRefPubMed

Fujiki H, Suganuma M (2011) Tumor promoters–microcystin-LR, nodularin and TNF-α and human cancer development. Anticancer Agents Med Chem 11(1):4–18CrossRefPubMed

Fujiki H, Sugimura T (1987) New classes of tumor promoters: teleocidin, aplysiatoxin, and palytoxin. Adv Cancer Res 49:223–264CrossRefPubMed

Fujiki H, Sueoka E, Suganuma M (2013) Tumor promoters: from chemicals to inflammatory proteins. J Cancer Res Clin Oncol 139(10):1603–1614CrossRefPubMed

Ginisty H, Sicard H, Roger B, Bouvet P (1999) Structure and functions of nucleolin. J Cell Sci 112(Pt 6):761–772PubMed

Hovanessian AG, Puvion-Dutilleul F, Nisole S, Svab J, Perret E, Deng JS, Krust B (2000) The cell-surface-expressed nucleolin is associated with the actin cytoskeleton. Exp Cell Res 261(2):312–328CrossRefPubMed

Hovanessian AG, Soundaramourty C, El Khoury D, Nondier I, Svab J, Krust B (2010) Surface expressed nucleolin is constantly induced in tumor cells to mediate calcium-dependent ligand internalization. PLoS One 5(12):e15787CrossRefPubMedPubMedCentral

Ireson CR, Kelland LR (2006) Discovery and development of anticancer aptamers. Mol Cancer Ther 5(12):2957–2962CrossRefPubMed

Jordan P, Heid H, Kinzel V, Kubler D (1994) Major cell surface-located protein substrates of an ecto-protein kinase are homologs of known nuclear proteins. Biochemistry (Mosc) 33(49):14696–14706CrossRef

Kadomatsu K, Muramatsu T (2004) Midkine and pleiotrophin in neural development and cancer. Cancer Lett 204(2):127–143CrossRefPubMed

Kato M, Takahashi M, Akhand AA, Liu W, Dai Y, Shimizu S, Iwamoto T, Suzuki H, Nakashima I (1998) Transgenic mouse model for skin malignant melanoma. Oncogene 17(14):1885–1888CrossRefPubMed

Keenan RJ, Freymann DM, Stroud RM, Walter P (2001) The signal recognition particle. Annu Rev Biochem 70:755–775CrossRefPubMed

Kirikoshi H, Katoh M (2002) Expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer. Int J Oncol 21(4):895–900PubMed

Kleinman HK, Weeks BS, Cannon FB, Sweeney TM, Sephel GC, Clement B, Zain M, Olson MO, Jucker M, Burrous BA (1991) Identification of a 110-kDa nonintegrin cell surface laminin-binding protein which recognizes an A chain neurite-promoting peptide. Arch Biochem Biophys 290(2):320–325CrossRefPubMed

Komori A, Yatsunami J, Suganuma M, Okabe S, Abe S, Sakai A, Sasaki K, Fujiki H (1993) Tumor necrosis factor acts as a tumor promoter in BALB/3T3 cell transformation. Cancer Res 53(9):1982–1985PubMed

Koutsioumpa M, Papadimitriou E (2013) Cell surface nucleolin as a target for anti-cancer therapies. Recent Pat Anticancer Drug Discov [Epub ahead of print]

Krantz S, Salazar R, Brandt R, Kellermann J, Lottspeich F (1995) Purification and partial amino acid sequencing of a fructosyllysine-specific binding protein from cell membranes of the monocyte-like cell line U937. Biochim Biophys Acta 1266(1):109–112CrossRefPubMed

Krust B, El Khoury D, Nondier I, Soundaramourty C, Hovanessian AG (2011a) Targeting surface nucleolin with multivalent HB-19 and related Nucant pseudopeptides results in distinct inhibitory mechanisms depending on the malignant tumor cell type. BMC Cancer 11:333CrossRefPubMedPubMedCentral

Krust B, El Khoury D, Soundaramourty C, Nondier I, Hovanessian AG (2011b) Suppression of tumorigenicity of rhabdoid tumor derived G401 cells by the multivalent HB-19 pseudopeptide that targets surface nucleolin. Biochimie 93(3):426–433CrossRefPubMed

Kuzuhara T, Suganuma M, Kurusu M, Fujiki H (2007) Helicobacter pylori-secreting protein Tipα is a potent inducer of chemokine gene expressions in stomach cancer cells. J Cancer Res Clin Oncol 133(5):287–296CrossRefPubMed

Larrucea S, González-Rubio C, Cambronero R, Ballou B, Bonay P, López-Granados E, Bouvet P, Fontán G, Fresno M, López-Trascasa M (1998) Cellular adhesion mediated by factor J, a complement inhibitor. Evidence for nucleolin involvement. J Biol Chem 273(43):31718–31725CrossRefPubMed

Legrand D, Vigié K, Said EA, Elass E, Masson M, Slomianny MC, Carpentier M, Briand JP, Mazurier J, Hovanessian AG (2004) Surface nucleolin participates in both the binding and endocytosis of lactoferrin in target cells. Eur J Biochem 271(2):303–317CrossRefPubMed

Losfeld ME, El Khoury D, Mariot P, Carpentier M, Krust B, Briand JP, Mazurier J, Hovanessian AG, Legrand D (2009) The cell surface expressed nucleolin is a glycoprotein that triggers calcium entry into mammalian cells. Exp Cell Res 315(2):357–369CrossRefPubMed

Lynch EM, Moreland RB, Ginis I, Perrine SP, Faller DV (2001) Hypoxia-activated ligand HAL-1/13 is lupus autoantigen Ku80 and mediates lymphoid cell adhesion in vitro. Am J Physiol Cell Physiol 280(4):C897–C911PubMed

Nisole S, Krust B, Callebaut C, Guichard G, Muller S, Briand JP, Hovanessian AG (1999) The anti-HIV pseudopeptide HB-19 forms a complex with the cell-surface-expressed nucleolin independent of heparan sulfate proteoglycans. J Biol Chem 274(39):27875–27884CrossRefPubMed

Nisole S, Said EA, Mische C, Prevost MC, Krust B, Bouvet P, Bianco A, Briand JP, Hovanessian AG (2002) The anti-HIV pentameric pseudopeptide HB-19 binds the C-terminal end of nucleolin and prevents anchorage of virus particles in the plasma membrane of target cells. J Biol Chem 277(23):20877–20886CrossRefPubMed

Ohshima Y, Yajima I, Takeda K, Iida M, Kumasaka M, Matsumoto Y, Kato M (2010) c-RET molecule in malignant melanoma from oncogenic RET-carrying transgenic mice and human cell lines. PLoS One 5(4):e10279CrossRefPubMedPubMedCentral

Orrick LR, Olson MO, Busch H (1973) Comparison of nucleolar proteins of normal rat liver and Novikoff hepatoma ascites cells by two-dimensional polyacrylamide gel electrophoresis. Proc Natl Acad Sci U S A 70(5):1316–1320CrossRefPubMedPubMedCentral

Ozawa D, Nakamura T, Koike M, Hirano K, Miki Y, Beppu M (2013) Shuttling protein nucleolin is a microglia receptor for amyloid beta peptide 1-42. Biol Pharm Bull 36(10):1587–1593CrossRefPubMed

Pfeifle J, Anderer FA (1983) Isolation and characterization of phosphoprotein pp 105 from simian virus 40-transformed mouse fibroblasts. Biochim Biophys Acta 762(1):86–93CrossRefPubMed

Pfeifle J, Hagmann W, Anderer FA (1981) Cell adhesion-dependent differences in endogenous protein phosphorylation on the surface of various cell lines. Biochim Biophys Acta 670(2):274–284CrossRefPubMed

Reyes-Reyes EM, Akiyama SK (2008) Cell-surface nucleolin is a signal transducing P-selectin binding protein for human colon carcinoma cells. Exp Cell Res 314(11–12):2212–2223CrossRefPubMedPubMedCentral

Rubinstein DB, Stortchevoi A, Boosalis M, Ashfaq R, Ghebrehiwet B, Peerschke EI, Calvo F, Guillaume T (2004) Receptor for the globular heads of C1q (gC1q-R, p33, hyaluronan-binding protein) is preferentially expressed by adenocarcinoma cells. Int J Cancer 110(5):741–750CrossRefPubMed

Semenkovich CF, Ostlund RE Jr, Olson MO, Yang JW (1990) A protein partially expressed on the surface of HepG2 cells that binds lipoproteins specifically is nucleolin. Biochemistry (Mosc) 29(41):9708–9713CrossRef

Shi H, Huang Y, Zhou H, Song X, Yuan S, Fu Y, Luo Y (2007) Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin. Blood 110(8):2899–2906CrossRefPubMed

Sinclair JF, O’Brien AD (2002) Cell surface-localized nucleolin is a eukaryotic receptor for the adhesin intimin-gamma of enterohemorrhagic Escherichia coli O157:H7. J Biol Chem 277(4):2876–2885CrossRefPubMed

Soundararajan S, Wang L, Sridharan V, Chen W, Courtenay-Luck N, Jones D, Spicer EK, Fernandes DJ (2009) Plasma membrane nucleolin is a receptor for the anticancer aptamer AS1411 in MV4-11 leukemia cells. Mol Pharmacol 76(5):984–991CrossRefPubMedPubMedCentral

Srivastava M, Pollard HB (1999) Molecular dissection of nucleolin’s role in growth and cell proliferation: new insights. FASEB J 13(14):1911–1922PubMed

Srivastava M, Fleming PJ, Pollard HB, Burns AL (1989) Cloning and sequencing of the human nucleolin cDNA. FEBS Lett 250(1):99–105CrossRefPubMed

Srivastava M, McBride OW, Fleming PJ, Pollard HB, Burns AL (1990) Genomic organization and chromosomal localization of the human nucleolin gene. J Biol Chem 265(25):14922–14931PubMed

Storck S, Thiry M, Bouvet P (2009) Conditional knockout of nucleolin in DT40 cells reveals the functional redundancy of its RNA-binding domains. Biol Cell 101(3):153–167CrossRefPubMed

Suganuma M, Okabe S, Marino MW, Sakai A, Sueoka E, Fujiki H (1999) Essential role of tumor necrosis factor α (TNF-α) in tumor promotion as revealed by TNF-α-deficient mice. Cancer Res 59(18):4516–4518PubMed

Suganuma M, Kurusu M, Okabe S, Sueoka N, Yoshida M, Wakatsuki Y, Fujiki H (2001) Helicobacter pylori membrane protein 1: a new carcinogenic factor of Helicobacter pylori. Cancer Res 61(17):6356–6359PubMed

Suganuma M, Okabe S, Kurusu M, Iida N, Ohshima S, Saeki Y, Kishimoto T, Fujiki H (2002) Discrete roles of cytokines, TNF-α IL-1, IL-6 in tumor promotion and cell transformation. Int J Oncol 20(1):131–136PubMed

Suganuma M, Kurusu M, Suzuki K, Nishizono A, Murakami K, Fujioka T, Fujiki H (2005) New tumor necrosis factor-α-inducing protein released from Helicobacter pylori for gastric cancer progression. J Cancer Res Clin Oncol 131(5):305–313CrossRefPubMed

Suganuma M, Yamaguchi K, Ono Y, Matsumoto H, Hayashi T, Ogawa T, Imai K, Kuzuhara T, Nishizono A, Fujiki H (2008) TNF-α-inducing protein, a carcinogenic factor secreted from H. pylori, enters gastric cancer cells. Int J Cancer 123(1):117–122CrossRefPubMed

Suganuma M, Watanabe T, Yamaguchi K, Takahashi A, Fujiki H (2012) Human gastric cancer development with TNF-α-inducing protein secreted from Helicobacter pylori. Cancer Lett 322(2):133–138CrossRefPubMed

Tate A, Isotani S, Bradley MJ, Sikes RA, Davis R, Chung LW, Edlund M (2006) Met-independent hepatocyte growth factor-mediated regulation of cell adhesion in human prostate cancer cells. BMC Cancer 6:197CrossRefPubMedPubMedCentral

Tayyari F, Marchant D, Moraes TJ, Duan W, Mastrangelo P, Hegele RG (2011) Identification of nucleolin as a cellular receptor for human respiratory syncytial virus. Nat Med 17(9):1132–1135CrossRefPubMed

Tsuge H, Tsurumura T, Utsunomiya H, Kise D, Kuzuhara T, Watanabe T, Fujiki H, Suganuma M (2009) Structural basis for the Helicobacter pylori-carcinogenic TNF-α-inducing protein. Biochem Biophys Res Commun 388(2):193–198CrossRefPubMed

Ugrinova I, Monier K, Ivaldi C, Thiry M, Storck S, Mongelard F, Bouvet P (2007) Inactivation of nucleolin leads to nucleolar disruption, cell cycle arrest and defects in centrosome duplication. BMC Mol Biol 8:66CrossRefPubMedPubMedCentral

Virchow R (1858) Reizung und Reizbarkeit. Arch pathol Anat u Physiol u klin Medizin 14:1–63

Watanabe T, Hirano K, Takahashi A, Yamaguchi K, Beppu M, Fujiki H, Suganuma M (2010a) Nucleolin on the cell surface as a new molecular target for gastric cancer treatment. Biol Pharm Bull 33(5):796–803CrossRefPubMed

Watanabe T, Tsuge H, Imagawa T, Kise D, Hirano K, Beppu M, Takahashi A, Yamaguchi K, Fujiki H, Suganuma M (2010b) Nucleolin as cell surface receptor for tumor necrosis factor-α inducing protein: a carcinogenic factor of Helicobacter pylori. J Cancer Res Clin Oncol 136(6):911–921CrossRefPubMed

Watanabe T, Takahashi A, Suzuki K, Kurusu-Kanno M, Yamaguchi K, Fujiki H, Suganuma M (2013) Epithelial-mesenchymal transition in human gastric cancer cell lines induced by TNF-α-inducing protein of Helicobacter pylori. Int J Cancer. doi:10.1002/ijc.28582 PubMedCentral

Yamagiwa K, Ichikawa K (1915) Experimentelle Studie über die Pathogenese der Epithelialgeschwülste. Mitteilungen Med Fakultät Kaiserl Univ Tokyo 15:295–344

Yoshida M, Wakatsuki Y, Kobayashi Y, Itoh T, Murakami K, Mizoguchi A, Usui T, Chiba T, Kita T (1999) Cloning and characterization of a novel membrane-associated antigenic protein of Helicobacter pylori. Infect Immun 67(1):286–293PubMedPubMedCentral

Title: Cell-surface nucleolin acts as a central mediator for carcinogenic, anti-carcinogenic, and disease-related ligands
Authors: Hirota Fujiki
Tatsuro Watanabe
Masami Suganuma
Publication date: 01-05-2014
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 5/2014
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-014-1587-5

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