Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Targeting Proliferating Cell Nuclear Antigen (PCNA) as an Effective Strategy to Inhibit Tumor Cell Proliferation

Author(s): Miriana Cardano, Carla Tribioli and Ennio Prosperi*

Volume 20, Issue 4, 2020

Page: [240 - 252] Pages: 13

DOI: 10.2174/1568009620666200115162814

Price: $65

Abstract

Targeting highly proliferating cells is an important issue for many types of aggressive tumors. Proliferating Cell Nuclear Antigen (PCNA) is an essential protein that participates in a variety of processes of DNA metabolism, including DNA replication and repair, chromatin organization and transcription and sister chromatid cohesion. In addition, PCNA is involved in cell survival, and possibly in pathways of energy metabolism, such as glycolysis. Thus, the possibility of targeting this protein for chemotherapy against highly proliferating malignancies is under active investigation. Currently, approaches to treat cells with agents targeting PCNA rely on the use of small molecules or on peptides that either bind to PCNA, or act as a competitor of interacting partners. Here, we describe the status of the art in the development of agents targeting PCNA and discuss their application in different types of tumor cell lines and in animal model systems.

Keywords: Proliferating Cell Nuclear Antigen (PCNA), drug target, tumor cell proliferation, peptides, small molecules, chemotherapy.

« Previous Next »
Graphical Abstract

[1]
Miyachi, K.; Fritzler, M.J.; Tan, E.M. Autoantibody to a nuclear antigen in proliferating cells. J. Immunol., 1978, 121(6), 2228-2234.
[PMID: 102692]
[2]
Bravo, R.; Celis, J.E. A search for differential polypeptide synthesis throughout the cell cycle of HeLa cells. J. Cell Biol., 1980, 84(3), 795-802.
[http://dx.doi.org/10.1083/jcb.84.3.795] [PMID: 6892640]
[3]
Bravo, R.; Fey, S.J.; Bellatin, J.; Larsen, P.M.; Arevalo, J.; Celis, J.E. Identification of a nuclear and of a cytoplasmic polypeptide whose relative proportions are sensitive to changes in the rate of cell proliferation. Exp. Cell Res., 1981, 136(2), 311-319.
[http://dx.doi.org/10.1016/0014-4827(81)90009-4] [PMID: 7308310]
[4]
Paunesku, T.; Mittal, S.; Protić, M.; Oryhon, J.; Korolev, S.V.; Joachimiak, A.; Woloschak, G.E. Proliferating cell nuclear antigen (PCNA): ringmaster of the genome. Int. J. Radiat. Biol., 2001, 77(10), 1007-1021.
[http://dx.doi.org/10.1080/09553000110069335] [PMID: 11682006]
[5]
Maga, G.; Hübscher, U. Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J. Cell Sci., 2003, 116(Pt 15), 3051-3060.
[http://dx.doi.org/10.1242/jcs.00653] [PMID: 12829735]
[6]
Moldovan, G.L.; Pfander, B.; Jentsch, S. PCNA, the maestro of the replication fork. Cell, 2007, 129(4), 665-679.
[http://dx.doi.org/10.1016/j.cell.2007.05.003] [PMID: 17512402]
[7]
Mailand, N.; Gibbs-Seymour, I.; Bekker-Jensen, S. Regulation of PCNA-protein interactions for genome stability. Nat. Rev. Mol. Cell Biol., 2013, 14(5), 269-282.
[http://dx.doi.org/10.1038/nrm3562] [PMID: 23594953]
[8]
Choe, K.N.; Moldovan, G.L. Forging ahead through darkness: PCNA, still the principal conductor at the replication fork. Mol. Cell, 2017, 65(3), 380-392.
[http://dx.doi.org/10.1016/j.molcel.2016.12.020] [PMID: 28157503]
[9]
Witko-Sarsat, V.; Mocek, J.; Bouayad, D.; Tamassia, N.; Ribeil, J.A.; Candalh, C.; Davezac, N.; Reuter, N.; Mouthon, L.; Hermine, O.; Pederzoli-Ribeil, M.; Cassatella, M.A. Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival. J. Exp. Med., 2010, 207(12), 2631-2645.
[http://dx.doi.org/10.1084/jem.20092241] [PMID: 20975039]
[10]
Naryzhny, S.N.; Lee, H. Proliferating cell nuclear antigen in the cytoplasm interacts with components of glycolysis and cancer. FEBS Lett., 2010, 584(20), 4292-4298.
[http://dx.doi.org/10.1016/j.febslet.2010.09.021] [PMID: 20849852]
[11]
Krishna, T.S.R.; Fenyö, D.; Kong, X.P.; Gary, S.; Chait, B.T.; Burgers, P.; Kuriyan, J. Crystallization of proliferating cell nuclear antigen (PCNA) from Saccharomyces cerevisiae. J. Mol. Biol., 1994, 241(2), 265-268.
[http://dx.doi.org/10.1006/jmbi.1994.1495] [PMID: 7914545]
[12]
Gulbis, J.M.; Kelman, Z.; Hurwitz, J.; O’Donnell, M.; Kuriyan, J. Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA. Cell, 1996, 87(2), 297-306.
[http://dx.doi.org/10.1016/S0092-8674(00)81347-1] [PMID: 8861913]
[13]
Schurtenberger, P.; Egelhaaf, S.U.; Hindges, R.; Maga, G.; Jónsson, Z.O.; May, R.P.; Glatter, O.; Hübscher, U. The solution structure of functionally active human proliferating cell nuclear antigen determined by small-angle neutron scattering. J. Mol. Biol., 1998, 275(1), 123-132.
[http://dx.doi.org/10.1006/jmbi.1997.1435] [PMID: 9451444]
[14]
Prosperi, E. The fellowship of the rings: distinct pools of proliferating cell nuclear antigen trimer at work. FASEB J., 2006, 20(7), 833-837.
[http://dx.doi.org/10.1096/fj.05-5469hyp] [PMID: 16675840]
[15]
Mondol, T.; Stodola, J.L.; Galletto, R.; Burgers, P.M. PCNA accelerates the nucleotide incorporation rate by DNA polymerase δ. Nucleic Acids Res., 2019, 47(4), 1977-1986.
[http://dx.doi.org/10.1093/nar/gky1321] [PMID: 30605530]
[16]
Warbrick, E. PCNA binding through a conserved motif. BioEssays, 1998, 20(3), 195-199.
[http://dx.doi.org/10.1002/(SICI)1521-1878(199803)20:3<195::AID-BIES2>3.0.CO;2-R] [PMID: 9631646]
[17]
Cazzalini, O.; Scovassi, A.I.; Savio, M.; Stivala, L.A.; Prosperi, E. Multiple roles of the cell cycle inhibitor p21(CDKN1A) in the DNA damage response. Mutat. Res., 2010, 704(1-3), 12-20.
[http://dx.doi.org/10.1016/j.mrrev.2010.01.009] [PMID: 20096807]
[18]
Havens, C.G.; Walter, J.C. Docking of a specialized PIP Box onto chromatin-bound PCNA creates a degron for the ubiquitin ligase CRL4Cdt2. Mol. Cell, 2009, 35(1), 93-104.
[http://dx.doi.org/10.1016/j.molcel.2009.05.012] [PMID: 19595719]
[19]
Havens, C.G.; Walter, J.C. Mechanism of CRL4(Cdt2), a PCNA-dependent E3 ubiquitin ligase. Genes Dev., 2011, 25(15), 1568-1582.
[http://dx.doi.org/10.1101/gad.2068611] [PMID: 21828267]
[20]
Gilljam, K.M.; Feyzi, E.; Aas, P.A.; Sousa, M.M.L.; Müller, R.; Vågbø, C.B.; Catterall, T.C.; Liabakk, N.B.; Slupphaug, G.; Drabløs, F.; Krokan, H.E.; Otterlei, M. Identification of a novel, widespread, and functionally important PCNA-binding motif. J. Cell Biol., 2009, 186(5), 645-654.
[http://dx.doi.org/10.1083/jcb.200903138] [PMID: 19736315]
[21]
Slade, D. Maneuvers on PCNA rings during DNA replication and repair. Genes (Basel), 2018, 9(8), 416.
[http://dx.doi.org/10.3390/genes9080416] [PMID: 30126151]
[22]
Naryzhny, S.N.; Lee, H. The post-translational modifications of proliferating cell nuclear antigen: acetylation, not phosphorylation, plays an important role in the regulation of its function. J. Biol. Chem., 2004, 279(19), 20194-20199.
[http://dx.doi.org/10.1074/jbc.M312850200] [PMID: 14988403]
[23]
Choudhary, C.; Kumar, C.; Gnad, F.; Nielsen, M.L.; Rehman, M.; Walther, T.C.; Olsen, J.V.; Mann, M. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science, 2009, 325(5942), 834-840.
[http://dx.doi.org/10.1126/science.1175371] [PMID: 19608861]
[24]
Prosperi, E.; Stivala, L.A.; Sala, E.; Scovassi, A.I.; Bianchi, L. Proliferating cell nuclear antigen complex formation induced by ultraviolet irradiation in human quiescent fibroblasts as detected by immunostaining and flow cytometry. Exp. Cell Res., 1993, 205(2), 320-325.
[http://dx.doi.org/10.1006/excr.1993.1092] [PMID: 8097724]
[25]
Wang, S.C.; Nakajima, Y.; Yu, Y.L.; Xia, W.; Chen, C.T.; Yang, C.C.; McIntush, E.W.; Li, L.Y.; Hawke, D.H.; Kobayashi, R.; Hung, M.C. Tyrosine phosphorylation controls PCNA function through protein stability. Nat. Cell Biol., 2006, 8(12), 1359-1368.
[http://dx.doi.org/10.1038/ncb1501] [PMID: 17115032]
[26]
Hoege, C.; Pfander, B.; Moldovan, G.L.; Pyrowolakis, G.; Jentsch, S. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature, 2002, 419(6903), 135-141.
[http://dx.doi.org/10.1038/nature00991] [PMID: 12226657]
[27]
Hoelz, D.J.; Arnold, R.J.; Dobrolecki, L.E.; Abdel-Aziz, W.; Loehrer, A.P.; Novotny, M.V.; Schnaper, L.; Hickey, R.J.; Malkas, L.H. The discovery of labile methyl esters on proliferating cell nuclear antigen by MS/MS. Proteomics, 2006, 6(17), 4808-4816.
[http://dx.doi.org/10.1002/pmic.200600142] [PMID: 16888766]
[28]
Yin, L.; Xie, Y.; Yin, S.; Lv, X.; Zhang, J.; Gu, Z.; Sun, H.; Liu, S. The S-nitrosylation status of PCNA localized in cytosol impacts the apoptotic pathway in a Parkinson’s disease paradigm. PLoS One, 2015, 10(2)e0117546
[http://dx.doi.org/10.1371/journal.pone.0117546] [PMID: 25675097]
[29]
Park, J.M.; Yang, S.W.; Yu, K.R.; Ka, S.H.; Lee, S.W.; Seol, J.H.; Jeon, Y.J.; Chung, C.H. Modification of PCNA by ISG15 plays a crucial role in termination of error-prone translesion DNA synthesis. Mol. Cell, 2014, 54(4), 626-638.
[http://dx.doi.org/10.1016/j.molcel.2014.03.031] [PMID: 24768535]
[30]
Yu, Y.; Cai, J.P.; Tu, B.; Wu, L.; Zhao, Y.; Liu, X.; Li, L.; McNutt, M.A.; Feng, J.; He, Q.; Yang, Y.; Wang, H.; Sekiguchi, M.; Zhu, W.G. Proliferating cell nuclear antigen is protected from degradation by forming a complex with MutT Homolog2. J. Biol. Chem., 2009, 284(29), 19310-19320.
[http://dx.doi.org/10.1074/jbc.M109.015289] [PMID: 19419956]
[31]
Cazzalini, O.; Sommatis, S.; Tillhon, M.; Dutto, I.; Bachi, A.; Rapp, A.; Nardo, T.; Scovassi, A.I.; Necchi, D.; Cardoso, M.C.; Stivala, L.A.; Prosperi, E. CBP and p300 acetylate PCNA to link its degradation with nucleotide excision repair synthesis. Nucleic Acids Res., 2014, 42(13), 8433-8448.
[http://dx.doi.org/10.1093/nar/gku533] [PMID: 24939902]
[32]
Prosperi, E.; Scovassi, A.I.; Stivala, L.A.; Bianchi, L. Proliferating cell nuclear antigen bound to DNA synthesis sites: phosphorylation and association with cyclin D1 and cyclin A. Exp. Cell Res., 1994, 215(2), 257-262.
[http://dx.doi.org/10.1006/excr.1994.1341] [PMID: 7982468]
[33]
Zhao, H.; Chen, M.S.; Lo, Y.H.; Waltz, S.E.; Wang, J.; Ho, P.C.; Vasiliauskas, J.; Plattner, R.; Wang, Y.L.; Wang, S.C. The Ron receptor tyrosine kinase activates c-Abl to promote cell proliferation through tyrosine phosphorylation of PCNA in breast cancer. Oncogene, 2014, 33(11), 1429-1437.
[http://dx.doi.org/10.1038/onc.2013.84] [PMID: 23542172]
[34]
Wang, S.C. PCNA: a silent housekeeper or a potential therapeutic target? Trends Pharmacol. Sci., 2014, 35(4), 178-186.
[http://dx.doi.org/10.1016/j.tips.2014.02.004] [PMID: 24655521]
[35]
Lehmann, A.R.; Niimi, A.; Ogi, T.; Brown, S.; Sabbioneda, S.; Wing, J.F.; Kannouche, P.L.; Green, C.M. Translesion synthesis: Y-family polymerases and the polymerase switch. DNA Repair (Amst.), 2007, 6(7), 891-899.
[http://dx.doi.org/10.1016/j.dnarep.2007.02.003] [PMID: 17363342]
[36]
Leung, W.; Baxley, R.M.; Moldovan, G.L.; Bielinsky, A.K. Mechanisms of DNA damage tolerance: Post-translational regulation of PCNA. Genes (Basel), 2018, 10(1), 10.
[http://dx.doi.org/10.3390/genes10010010] [PMID: 30586904]
[37]
Johnson, A.; O’Donnell, M. Cellular DNA replicases: components and dynamics at the replication fork. Annu. Rev. Biochem., 2005, 74, 283-315.
[http://dx.doi.org/10.1146/annurev.biochem.73.011303.073859] [PMID: 15952889]
[38]
Boehm, E.M.; Gildenberg, M.S.; Washington, M.T. The many roles of PCNA in eukaryotic DNA replication. Enzymes, 2016, 39, 231-254.
[http://dx.doi.org/10.1016/bs.enz.2016.03.003] [PMID: 27241932]
[39]
Stodola, J.L.; Burgers, P.M. Mechanism of lagging-strand DNA replication in eukaryotes. Adv. Exp. Med. Biol., 2017, 1042, 117-133.
[http://dx.doi.org/10.1007/978-981-10-6955-0_6] [PMID: 29357056]
[40]
Lee, K.Y.; Fu, H.; Aladjem, M.I.; Myung, K. ATAD5 regulates the lifespan of DNA replication factories by modulating PCNA level on the chromatin. J. Cell Biol., 2013, 200(1), 31-44.
[http://dx.doi.org/10.1083/jcb.201206084] [PMID: 23277426]
[41]
Kubota, T.; Nishimura, K.; Kanemaki, M.T.; Donaldson, A.D. The Elg1 replication factor C-like complex functions in PCNA unloading during DNA replication. Mol. Cell, 2013, 50(2), 273-280.
[http://dx.doi.org/10.1016/j.molcel.2013.02.012] [PMID: 23499004]
[42]
Yu, C.; Gan, H.; Han, J.; Zhou, Z.X.; Jia, S.; Chabes, A.; Farrugia, G.; Ordog, T.; Zhang, Z. Strand-specific analysis shows protein binding at replication forks and PCNA unloading from lagging strands when forks stall. Mol. Cell, 2014, 56(4), 551-563.
[http://dx.doi.org/10.1016/j.molcel.2014.09.017] [PMID: 25449133]
[43]
Marteijn, J.A.; Lans, H.; Vermeulen, W.; Hoeijmakers, J.H.J. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat. Rev. Mol. Cell Biol., 2014, 15(7), 465-481.
[http://dx.doi.org/10.1038/nrm3822] [PMID: 24954209]
[44]
Ogi, T.; Limsirichaikul, S.; Overmeer, R.M.; Volker, M.; Takenaka, K.; Cloney, R.; Nakazawa, Y.; Niimi, A.; Miki, Y.; Jaspers, N.G.; Mullenders, L.H.; Yamashita, S.; Fousteri, M.I.; Lehmann, A.R. Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells. Mol. Cell, 2010, 37(5), 714-727.
[http://dx.doi.org/10.1016/j.molcel.2010.02.009] [PMID: 20227374]
[45]
Hong, R.; Chakravarti, D. The human proliferating Cell nuclear antigen regulates transcriptional coactivator p300 activity and promotes transcriptional repression. J. Biol. Chem., 2003, 278(45), 44505-44513.
[http://dx.doi.org/10.1074/jbc.M303138200] [PMID: 12937166]
[46]
Cazzalini, O.; Perucca, P.; Savio, M.; Necchi, D.; Bianchi, L.; Stivala, L.A.; Ducommun, B.; Scovassi, A.I.; Prosperi, E. Interaction of p21(CDKN1A) with PCNA regulates the histone acetyltransferase activity of p300 in nucleotide excision repair. Nucleic Acids Res., 2008, 36(5), 1713-1722.
[http://dx.doi.org/10.1093/nar/gkn014] [PMID: 18263614]
[47]
Tillhon, M.; Cazzalini, O.; Nardo, T.; Necchi, D.; Sommatis, S.; Stivala, L.A.; Scovassi, A.I.; Prosperi, E. p300/CBP acetyl transferases interact with and acetylate the nucleotide excision repair factor XPG. DNA Repair (Amst.), 2012, 11(10), 844-852.
[http://dx.doi.org/10.1016/j.dnarep.2012.08.001] [PMID: 22954786]
[48]
Dutto, I.; Scalera, C.; Prosperi, E. CREBBP and p300 lysine acetyl transferases in the DNA damage response. Cell. Mol. Life Sci., 2018, 75(8), 1325-1338.
[http://dx.doi.org/10.1007/s00018-017-2717-4] [PMID: 29170789]
[49]
Krokan, H.E.; Bjørås, M. Base excision repair. Cold Spring Harb. Perspect. Biol., 2013, 5(4)a012583
[http://dx.doi.org/10.1101/cshperspect.a012583] [PMID: 23545420]
[50]
Fortini, P.; Dogliotti, E. Base damage and single-strand break repair: mechanisms and functional significance of short- and long-patch repair subpathways. DNA Repair (Amst.), 2007, 6(4), 398-409.
[http://dx.doi.org/10.1016/j.dnarep.2006.10.008] [PMID: 17129767]
[51]
Moor, N.A.; Lavrik, O.I. Protein-protein interactions in DNA base excision repair. Biochemistry (Mosc.), 2018, 83(4), 411-422.
[http://dx.doi.org/10.1134/S0006297918040120] [PMID: 29626928]
[52]
Modrich, P. Mechanisms in eukaryotic mismatch repair. J. Biol. Chem., 2006, 281(41), 30305-30309.
[http://dx.doi.org/10.1074/jbc.R600022200] [PMID: 16905530]
[53]
Li, G.M. Mechanisms and functions of DNA mismatch repair. Cell Res., 2008, 18(1), 85-98.
[http://dx.doi.org/10.1038/cr.2007.115] [PMID: 18157157]
[54]
Li, X.; Stith, C.M.; Burgers, P.M.; Heyer, W.D. PCNA is required for initiation of recombination-associated DNA synthesis by DNA polymerase δ. Mol. Cell, 2009, 36(4), 704-713.
[http://dx.doi.org/10.1016/j.molcel.2009.09.036] [PMID: 19941829]
[55]
He, G.; Kuang, J.; Koomen, J.; Kobayashi, R.; Khokhar, A.R.; Siddik, Z.H. Recruitment of trimeric proliferating cell nuclear antigen by G1-phase cyclin-dependent kinases following DNA damage with platinum-based antitumour agents. Br. J. Cancer, 2013, 109(9), 2378-2388.
[http://dx.doi.org/10.1038/bjc.2013.613] [PMID: 24104967]
[56]
Arias, E.E.; Walter, J.C. PCNA functions as a molecular platform to trigger Cdt1 destruction and prevent re-replication. Nat. Cell Biol., 2006, 8(1), 84-90.
[http://dx.doi.org/10.1038/ncb1346] [PMID: 16362051]
[57]
Cazzalini, O.; Perucca, P.; Riva, F.; Stivala, L.A.; Bianchi, L.; Vannini, V.; Ducommun, B.; Prosperi, E. p21CDKN1A does not interfere with loading of PCNA at DNA replication sites, but inhibits subsequent binding of DNA polymerase delta at the G1/S phase transition. Cell Cycle, 2003, 2(6), 596-603.
[http://dx.doi.org/10.4161/cc.2.6.502] [PMID: 14504476]
[58]
De Chiara, A.; Pederzoli-Ribeil, M.; Mocek, J.; Candalh, C.; Mayeux, P.; Millet, A.; Witko-Sarsat, V. Characterization of cytosolic proliferating cell nuclear antigen (PCNA) in neutrophils: antiapoptotic role of the monomer. J. Leukoc. Biol., 2013, 94(4), 723-731.
[http://dx.doi.org/10.1189/jlb.1212637] [PMID: 23825390]
[59]
Ohayon, D.; De Chiara, A.; Chapuis, N.; Candalh, C.; Mocek, J.; Ribeil, J.A.; Haddaoui, L.; Ifrah, N.; Hermine, O.; Bouillaud, F.; Frachet, P.; Bouscary, D.; Witko-Sarsat, V. Cytoplasmic proliferating cell nuclear antigen connects glycolysis and cell survival in acute myeloid leukemia. Sci. Rep., 2016, 6, 35561.
[http://dx.doi.org/10.1038/srep35561] [PMID: 27759041]
[60]
Ohayon, D.; De Chiara, A.; Dang, P.M.; Thieblemont, N.; Chatfield, S.; Marzaioli, V.; Burgener, S.S.; Mocek, J.; Candalh, C.; Pintard, C.; Tacnet-Delorme, P.; Renault, G.; Lagoutte, I.; Favier, M.; Walker, F.; Hurtado-Nedelec, M.; Desplancq, D.; Weiss, E.; Benarafa, C.; Housset, D.; Marie, J.C.; Frachet, P.; El-Benna, J.; Witko-Sarsat, V. Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils. J. Exp. Med., 2019, 216(11), 2669-2687.
[http://dx.doi.org/10.1084/jem.20180371]
[61]
Lindström, M.; Wallin, K.L. Prognostic role of proliferating cell nuclear antigen (PCNA) in cancer and other diseases.Proliferating Cell Nuclear Antigen (PCNA); Lee, H., Ed.; Research Signpost: Kerala, 2005, pp. 181-204.
[62]
Stoimenov, I.; Helleday, T. PCNA on the crossroad of cancer. Biochem. Soc. Trans., 2009, 37(Pt 3), 605-613.
[http://dx.doi.org/10.1042/BST0370605] [PMID: 19442257]
[63]
Stoimenov, I.; Helleday, T. PCNA (proliferating cell nuclear antigen). Atlas Genet. Cytogenet. Oncol. Haematol., 2012, 16, 208-1154.
[64]
Bechtel, P.E.; Hickey, R.J.; Schnaper, L.; Sekowski, J.W.; Long, B.J.; Freund, R.; Liu, N.; Rodriguez-Valenzuela, C.; Malkas, L.H. A unique form of proliferating cell nuclear antigen is present in malignant breast cells. Cancer Res., 1998, 58(15), 3264-3269.
[PMID: 9699653]
[65]
Yang, J.; Chen, Z.; Liu, Y.; Hickey, R.J.; Malkas, L.H. Altered DNA polymerase iota expression in breast cancer cells leads to a reduction in DNA replication fidelity and a higher rate of mutagenesis. Cancer Res., 2004, 64(16), 5597-5607.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-0603] [PMID: 15313897]
[66]
Venturi, A.; Piaz, F.D.; Giovannini, C.; Gramantieri, L.; Chieco, P.; Bolondi, L. Human hepatocellular carcinoma expresses specific PCNA isoforms: an in vivo and in vitro evaluation. Lab. Invest., 2008, 88(9), 995-1007.
[http://dx.doi.org/10.1038/labinvest.2008.50] [PMID: 18521065]
[67]
Kracmarova, A.; Cermak, J.; Brdicka, R.; Bruchova, H. High expression of ERCC1, FLT1, NME4 and PCNA associated with poor prognosis and advanced stages in myelodysplastic syndrome. Leuk. Lymphoma, 2008, 49(7), 1297-1305.
[http://dx.doi.org/10.1080/10428190802129918] [PMID: 18604718]
[68]
Sun, W.; Xing, B.; Sun, Y.; Du, X.; Lu, M.; Hao, C.; Lu, Z.; Mi, W.; Wu, S.; Wei, H.; Gao, X.; Zhu, Y.; Jiang, Y.; Qian, X.; He, F. Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues. Mol. Cell. Proteomics, 2007, 6(10), 1798-1808.
[http://dx.doi.org/10.1074/mcp.M600449-MCP200] [PMID: 17627933]
[69]
Yin, S.; Li, Z.; Huang, J.; Miao, Z.; Zhang, J.; Lu, C.; Xu, H.; Xu, H. Prognostic value and clinicopathological significance of proliferating cell nuclear antigen expression in gastric cancer: a systematic review and meta-analysis. OncoTargets Ther., 2017, 10, 319-327.
[http://dx.doi.org/10.2147/OTT.S126551] [PMID: 28138255]
[70]
Altieri, A.S.; Kelman, Z. DNA sliding clamps as therapeutics targets. Front. Mol. Biosci., 2018, 5, 87.
[http://dx.doi.org/10.3389/fmolb.2018.00087] [PMID: 30406112]
[71]
Warbrick, E. A functional analysis of PCNA-binding peptides derived from protein sequence, interaction screening and rational design. Oncogene, 2006, 25(20), 2850-2859.
[http://dx.doi.org/10.1038/sj.onc.1209320] [PMID: 16407840]
[72]
Chen, J.; Peters, R.; Saha, P.; Lee, P.; Theodoras, A.; Pagano, M.; Wagner, G.; Dutta, A. A 39 amino acid fragment of the cell cycle regulator p21 is sufficient to bind PCNA and partially inhibit DNA replication in vivo. Nucleic Acids Res., 1996, 24(9), 1727-1733.
[http://dx.doi.org/10.1093/nar/24.9.1727] [PMID: 8649992]
[73]
Smith, S.J.; Hickey, R.J.; Malkas, L.H. Validating the disruption of proliferating cell nuclear antigen interactions in the development of targeted cancer therapeutics. Cancer Biol. Ther., 2016, 17(3), 310-319.
[http://dx.doi.org/10.1080/15384047.2016.1139247] [PMID: 26889573]
[74]
Dong, C.; Lyu, S.C.; Krensky, A.M.; Clayberger, C. DQ 65-79, a peptide derived from HLA class II, mimics p21 to block T cell proliferation. J. Immunol., 2003, 171(10), 5064-5070.
[http://dx.doi.org/10.4049/jimmunol.171.10.5064] [PMID: 14607903]
[75]
Shemesh, A.; Kundu, K.; Peleg, R.; Yossef, R.; Kaplanov, I.; Ghosh, S.; Khrapunsky, Y.; Gershoni-Yahalom, O.; Rabinski, T.; Cerwenka, A.; Atlas, R.; Porgador, A. NKp44-derived peptide binds proliferating cell nuclear antigen and mediates tumor cell death. Front. Immunol., 2018, 9, 1114.
[http://dx.doi.org/10.3389/fimmu.2018.01114] [PMID: 29875773]
[76]
Warbrick, E.; Lane, D.P.; Glover, D.M.; Cox, L.S. A small peptide inhibitor of DNA replication defines the site of interaction between the cyclin-dependent kinase inhibitor p21WAF1 and proliferating cell nuclear antigen. Curr. Biol., 1995, 5(3), 275-282.
[http://dx.doi.org/10.1016/S0960-9822(95)00058-3] [PMID: 7780738]
[77]
Kontopidis, G.; Wu, S.Y.; Zheleva, D.I.; Taylor, P.; McInnes, C.; Lane, D.P.; Fischer, P.M.; Walkinshaw, M.D. Structural and biochemical studies of human proliferating cell nuclear antigen complexes provide a rationale for cyclin association and inhibitor design. Proc. Natl. Acad. Sci. USA, 2005, 102(6), 1871-1876.
[http://dx.doi.org/10.1073/pnas.0406540102] [PMID: 15681588]
[78]
Mattock, H.; Lane, D.P.; Warbrick, E. Inhibition of cell proliferation by the PCNA-binding region of p21 expressed as a GFP miniprotein. Exp. Cell Res., 2001, 265(2), 234-241.
[http://dx.doi.org/10.1006/excr.2001.5160] [PMID: 11302688]
[79]
Zheleva, D.I.; Zhelev, N.Z.; Fischer, P.M.; Duff, S.V.; Warbrick, E.; Blake, D.G.; Lane, D.P. A quantitative study of the in vitro binding of the C-terminal domain of p21 to PCNA: affinity, stoichiometry, and thermodynamics. Biochemistry, 2000, 39(25), 7388-7397.
[http://dx.doi.org/10.1021/bi992498r] [PMID: 10858286]
[80]
Wegener, K.L.; McGrath, A.E.; Dixon, N.E.; Oakley, A.J.; Scanlon, D.B.; Abell, A.D.; Bruning, J.B. Rational design of a 310 -helical PIP-Box mimetic targeting PCNA, the human sliding clamp. Chemistry, 2018, 24(44), 11325-11331.
[http://dx.doi.org/10.1002/chem.201801734] [PMID: 29917264]
[81]
Müller, R.; Misund, K.; Holien, T.; Bachke, S.; Gilljam, K.M.; Våtsveen, T.K.; Rø, T.B.; Bellacchio, E.; Sundan, A.; Otterlei, M. Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells. PLoS One, 2013, 8(7)e70430
[http://dx.doi.org/10.1371/journal.pone.0070430] [PMID: 23936203]
[82]
Gederaas, O.A.; Søgaard, C.D.; Viset, T.; Bachke, S.; Bruheim, P.; Arum, C.J.; Otterlei, M. Increased anticancer efficacy of intravesical mitomycin C therapy when combined with a PCNA targeting peptide. Transl. Oncol., 2014, 7(6), 812-823.
[http://dx.doi.org/10.1016/j.tranon.2014.10.005] [PMID: 25500092]
[83]
Baglo, Y.; Hagen, L.; Høgset, A.; Drabløs, F.; Otterlei, M.; Gederaas, O.A. Enhanced efficacy of bleomycin in bladder cancer cells by photochemical internalization. BioMed Res. Int., 2014, 2014921296
[http://dx.doi.org/10.1155/2014/921296] [PMID: 25101299]
[84]
Søgaard, C.K.; Blindheim, A.; Røst, L.M.; Petrović, V.; Nepal, A.; Bachke, S.; Liabakk, N.B.; Gederaas, O.A.; Viset, T.; Arum, C.J.; Bruheim, P.; Otterlei, M. “Two hits - one stone”; increased efficacy of cisplatin-based therapies by targeting PCNA’s role in both DNA repair and cellular signaling. Oncotarget, 2018, 9(65), 32448-32465.
[http://dx.doi.org/10.18632/oncotarget.25963] [PMID: 30197755]
[85]
Olaisen, C.; Müller, R.; Nedal, A.; Otterlei, M. PCNA-interacting peptides reduce Akt phosphorylation and TLR-mediated cytokine secretion suggesting a role of PCNA in cellular signaling. Cell. Signal., 2015, 27(7), 1478-1487.
[http://dx.doi.org/10.1016/j.cellsig.2015.03.009] [PMID: 25797046]
[86]
Søgaard, C.K.; Moestue, S.A.; Rye, M.B.; Kim, J.; Nepal, A.; Liabakk, N.B.; Bachke, S.; Bathen, T.F.; Otterlei, M.; Hill, D.K. APIM-peptide targeting PCNA improves the efficacy of docetaxel treatment in the TRAMP mouse model of prostate cancer. Oncotarget, 2018, 9(14), 11752-11766.
[http://dx.doi.org/10.18632/oncotarget.24357] [PMID: 29545934]
[87]
Smith, S.J.; Gu, L.; Phipps, E.A.; Dobrolecki, L.E.; Mabrey, K.S.; Gulley, P.; Dillehay, K.L.; Dong, Z.; Fields, G.B.; Chen, Y-R.; Ann, D.; Hickey, R.J.; Malkas, L.H. A Peptide mimicking a region in proliferating cell nuclear antigen specific to key protein interactions is cytotoxic to breast cancer. Mol. Pharmacol., 2015, 87(2), 263-276.
[http://dx.doi.org/10.1124/mol.114.093211] [PMID: 25480843]
[88]
Malkas, L.H.; Herbert, B.S.; Abdel-Aziz, W.; Dobrolecki, L.E.; Liu, Y.; Agarwal, B.; Hoelz, D.; Badve, S.; Schnaper, L.; Arnold, R.J.; Mechref, Y.; Novotny, M.V.; Loehrer, P.; Goulet, R.J.; Hickey, R.J. A cancer-associated PCNA expressed in breast cancer has implications as a potential biomarker. Proc. Natl. Acad. Sci. USA, 2006, 103(51), 19472-19477.
[http://dx.doi.org/10.1073/pnas.0604614103] [PMID: 17159154]
[89]
Sandoval, J.A.; Hickey, R.J.; Malkas, L.H. Isolation and characterization of a DNA synthesome from a neuroblastoma cell line. J. Pediatr. Surg., 2005, 40(7), 1070-1077.
[http://dx.doi.org/10.1016/j.jpedsurg.2005.03.054] [PMID: 16034747]
[90]
Wang, X.; Hickey, R.J.; Malkas, L.H.; Koch, M.O.; Li, L.; Zhang, S.; Sandusky, G.E.; Grignon, D.J.; Eble, J.N.; Cheng, L. Elevated expression of cancer-associated proliferating cell nuclear antigen in high-grade prostatic intraepithelial neoplasia and prostate cancer. Prostate, 2011, 71(7), 748-754.
[http://dx.doi.org/10.1002/pros.21291] [PMID: 21031434]
[91]
Gu, L.; Smith, S.; Li, C.; Hickey, R.J.; Stark, J.M.; Fields, G.B.; Lang, W.H.; Sandoval, J.A.; Malkas, L.H. A PCNA-derived cell permeable peptide selectively inhibits neuroblastoma cell growth. PLoS One, 2014, 9(4): e94773
[http://dx.doi.org/10.1371/journal.pone.0094773] [PMID: 24728180]
[92]
Gu, L.; Chu, P.; Lingeman, R.; McDaniel, H.; Kechichian, S.; Hickey, R.J.; Liu, Z.; Yuan, Y.C.; Sandoval, J.A.; Fields, G.B.; Malkas, L.H. The mechanism by which MYCN amplification confers an enhanced sensitivity to a PCNA-derived cell permeable peptide in neuroblastoma cells. EBioMedicine, 2015, 2(12), 1923-1931.
[http://dx.doi.org/10.1016/j.ebiom.2015.11.016] [PMID: 26844271]
[93]
Lingeman, R.G.; Hickey, R.J.; Malkas, L.H. Expression of a novel peptide derived from PCNA damages DNA and reverses cisplatin resistance. Cancer Chemother. Pharmacol., 2014, 74(5), 981-993.
[http://dx.doi.org/10.1007/s00280-014-2574-x] [PMID: 25190177]
[94]
Zhao, H.; Lo, Y.H.; Ma, L.; Waltz, S.E.; Gray, J.K.; Hung, M.C.; Wang, S.C. Targeting tyrosine phosphorylation of PCNA inhibits prostate cancer growth. Mol. Cancer Ther., 2011, 10(1), 29-36.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0778] [PMID: 21220489]
[95]
Zhao, H.; Ho, P.C.; Lo, Y.H.; Espejo, A.; Bedford, M.T.; Hung, M.C.; Wang, S.C. Interaction of proliferation cell nuclear antigen (PCNA) with c-Abl in cell proliferation and response to DNA damages in breast cancer. PLoS One, 2012, 7(1), e29416
[http://dx.doi.org/10.1371/journal.pone.0029416] [PMID: 22238610]
[96]
Yu, Y.L.; Chou, R.H.; Liang, J.H.; Chang, W.J.; Su, K.J.; Tseng, Y.J.; Huang, W.C.; Wang, S.C.; Hung, M.C. Targeting the EGFR/PCNA signaling suppresses tumor growth of triple-negative breast cancer cells with cell-penetrating PCNA peptides. PLoS One, 2013, 8(4), e61362
[http://dx.doi.org/10.1371/journal.pone.0061362] [PMID: 23593472]
[97]
Rosental, B.; Brusilovsky, M.; Hadad, U.; Oz, D.; Appel, M.Y.; Afergan, F.; Yossef, R.; Rosenberg, L.A.; Aharoni, A.; Cerwenka, A.; Campbell, K.S.; Braiman, A.; Porgador, A. Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44. J. Immunol., 2011, 187(11), 5693-5702.
[http://dx.doi.org/10.4049/jimmunol.1102267] [PMID: 22021614]
[98]
Punchihewa, C.; Inoue, A.; Hishiki, A.; Fujikawa, Y.; Connelly, M.; Evison, B.; Shao, Y.; Heath, R.; Kuraoka, I.; Rodrigues, P.; Hashimoto, H.; Kawanishi, M.; Sato, M.; Yagi, T.; Fujii, N. Identification of small molecule proliferating cell nuclear antigen (PCNA) inhibitor that disrupts interactions with PIP-box proteins and inhibits DNA replication. J. Biol. Chem., 2012, 287(17), 14289-14300.
[http://dx.doi.org/10.1074/jbc.M112.353201] [PMID: 22383522]
[99]
Inoue, A.; Kikuchi, S.; Hishiki, A.; Shao, Y.; Heath, R.; Evison, B.J.; Actis, M.; Canman, C.E.; Hashimoto, H.; Fujii, N. A small molecule inhibitor of monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA) inhibits repair of interstrand DNA cross-link, enhances DNA double strand break, and sensitizes cancer cells to cisplatin. J. Biol. Chem., 2014, 289(10), 7109-7120.
[http://dx.doi.org/10.1074/jbc.M113.520429] [PMID: 24474685]
[100]
Actis, M.; Inoue, A.; Evison, B.; Perry, S.; Punchihewa, C.; Fujii, N. Small molecule inhibitors of PCNA/PIP-box interaction suppress translesion DNA synthesis. Bioorg. Med. Chem., 2013, 21(7), 1972-1977.
[http://dx.doi.org/10.1016/j.bmc.2013.01.022] [PMID: 23395113]
[101]
Evison, B.J.; Actis, M.L.; Wu, S.Z.; Shao, Y.; Heath, R.J.; Yang, L.; Fujii, N. A site-selective, irreversible inhibitor of the DNA replication auxiliary factor proliferating cell nuclear antigen (PCNA). Bioorg. Med. Chem., 2014, 22(22), 6333-6343.
[http://dx.doi.org/10.1016/j.bmc.2014.09.058] [PMID: 25438756]
[102]
Wilson, R.H.; Biasutto, A.J.; Wang, L.; Fischer, R.; Baple, E.L.; Crosby, A.H.; Mancini, E.J.; Green, C.M. PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions. DNA Repair (Amst.), 2017, 50(2), 22-35.
[http://dx.doi.org/10.1016/j.dnarep.2016.12.003] [PMID: 28073635]
[103]
Gu, L.; Lingeman, R.; Yakushijin, F.; Sun, E.; Cui, Q.; Chao, J.; Hu, W.; Li, H.; Hickey, R.J.; Stark, J.M.; Yuan, Y.C.; Chen, Y.; Vonderfecht, S.L.; Synold, T.W.; Shi, Y.; Reckamp, K.L.; Horne, D.; Malkas, L.H. The anticancer activity of a first-in-class small-molecule targeting PCNA. Clin. Cancer Res., 2018, 24(23), 6053-6065.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-0592] [PMID: 29967249]
[104]
Li, W.; Zhou, Y.; Tang, G.; Wong, N.K.; Yang, M.; Tan, D.; Xiao, Y. Chemoproteomics reveals the antiproliferative potential of Parkinson’s disease kinase inhibitor LRRK2-IN-1 by targeting PCNA protein. Mol. Pharm., 2018, 15(8), 3252-3259.
[http://dx.doi.org/10.1021/acs.molpharmaceut.8b00325] [PMID: 29993254]
[105]
Tan, Z.; Wortman, M.; Dillehay, K.L.; Seibel, W.L.; Evelyn, C.R.; Smith, S.J.; Malkas, L.H.; Zheng, Y.; Lu, S.; Dong, Z. Small-molecule targeting of proliferating cell nuclear antigen chromatin association inhibits tumor cell growth. Mol. Pharmacol., 2012, 81(6), 811-819.
[http://dx.doi.org/10.1124/mol.112.077735] [PMID: 22399488]
[106]
Dillehay, K.L.; Lu, S.; Dong, Z. Antitumor effects of a novel small molecule targeting PCNA chromatin association in prostate cancer. Mol. Cancer Ther., 2014, 13(12), 2817-2826.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0522] [PMID: 25253786]
[107]
Dillehay, K.L.; Seibel, W.L.; Zhao, D.; Lu, S.; Dong, Z. Target validation and structure-activity analysis of a series of novel PCNA inhibitors. Pharmacol. Res. Perspect., 2015, 3(2), e00115
[http://dx.doi.org/10.1002/prp2.115] [PMID: 25729582]
[108]
Altieri, A.S.; Ladner, J.E.; Li, Z.; Robinson, H.; Sallman, Z.F.; Marino, J.P.; Kelman, Z. A small protein inhibits proliferating cell nuclear antigen by breaking the DNA clamp. Nucleic Acids Res., 2016, 44(13), 6232-6241.
[http://dx.doi.org/10.1093/nar/gkw351] [PMID: 27141962]
[109]
Kowalska, E.; Bartnicki, F.; Fujisawa, R.; Bonarek, P.; Hermanowicz, P.; Tsurimoto, T.; Muszynska, K.; Strzalka, W. Inhibition of DNA replication by an anti-PCNA aptamer/PCNA complex. Nucleic Acids Res., 2018, 46(1), 25-41.
[http://dx.doi.org/10.1093/nar/gkx1184] [PMID: 29186524]
[110]
Horsfall, A.J.; Abell, A.D.; Bruning, J.B. Targeting PCNA with peptide mimetics for therapeutic purposes. ChemBioChem, Epub Ahead of Print
[http://dx.doi.org/10.1002/cbic.201900275] [PMID: 31247123]
[111]
Cirillo, D.; Pentimalli, F.; Giordano, A. Peptides or small molecules? Different approaches to develop more effective CDK inhibitors. Curr. Med. Chem., 2011, 18(19), 2854-2866.
[http://dx.doi.org/10.2174/092986711796150496] [PMID: 21651493]
[112]
De March, M.; De Biasio, A. The dark side of the ring: role of the DNA sliding surface of PCNA. Crit. Rev. Biochem. Mol. Biol., 2017, 52(6), 663-673.
[http://dx.doi.org/10.1080/10409238.2017.1364218] [PMID: 28814116]
[113]
Billon, P.; Côté, J. Novel mechanism of PCNA control through acetylation of its sliding surface. Mol. Cell. Oncol., 2017, 4(2), e1279724
[http://dx.doi.org/10.1080/23723556.2017.1279724] [PMID: 28401185]

Rights & Permissions Print Cite
Article Metrics
268
23
2
2
© 2024 Bentham Science Publishers | Privacy Policy