STAT3: A Potential Drug Target for Tumor and Inflammation

Author(s): Yang Sheng Hu , Xu Han , Xin Hua Liu* .

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 15 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

STAT (Signal Transducers and Activators of Transcription) is a cellular signal transcription factor involved in the regulation of many cellular activities, such as cell differentiation, proliferation, angiogenesis in normal cells. During the study of the STAT family, STAT3 was found to be involved in many diseases, such as high expression and sustained activation of STAT3 in tumor cells, promoting tumor growth and proliferation. In the study of inflammation, it was found that it plays an important role in the anti-inflammatory and repairing of damage tissues. Because of the important role of STAT3, a large number of studies have been obtained. At the same time, after more than 20 years of development, STAT3 has also been used as a target for drug therapy. And the discovery of small molecule inhibitors also promoted the study of STAT3. Since STAT3 has been extensively studied in inflammation and tumor regulation, this review presents the current state of research on STAT3.

Keywords: STAT 3, Anti-tumor, Inflammation, Inhibitor, Function, Target.

[1]
Becker, S.; Groner, B.; Müller, C.W. Three-dimensional structure of the Stat3β homodimer bound to DNA. Nature, 1998, 394(6689), 145-151. [http://dx.doi.org/10.1038/28101]. [PMID: 9671298].
[2]
Ihle, J.N. STATs: Signal transducers and activators of transcription. Cell, 1996, 84(3), 331-334. [http://dx.doi.org/10.1016/S0092-8674(00)81277-5]. [PMID: 8608586].
[3]
Darnell, J.E. STATs and gene regulation. Science, 1997, 277(5332), 1630-1635. [http://dx.doi.org/10.1126/science.277.5332.1630]. [PMID: 9287210].
[4]
Rawlings, J.S.; Rosler, K.M.; Harrison, D.A. The JAK/STAT signaling pathway. J. Cell Sci., 2004, 117(Pt 8), 1281-1283. [http://dx.doi.org/10.1242/jcs.00963]. [PMID: 15020666].
[5]
Chowdhury, F.Z.; Farrar, J.D. STAT2: A shape-shifting anti-viral super STAT. JAK-STAT, 2013, 2(1), e23633. [http://dx.doi.org/10.4161/jkst.23633]. [PMID: 24058798].
[6]
Horvath, C.M. STAT proteins and transcriptional responses to extracellular signals. Trends Biochem. Sci., 2000, 25(10), 496-502. [http://dx.doi.org/10.1016/S0968-0004(00)01624-8]. [PMID: 11050435].
[7]
Xiong, A.; Yang, Z.; Shen, Y.; Zhou, J.; Shen, Q. Transcription Factor STAT3 as a novel molecular target for cancer prevention. Cancers (Basel), 2014, 6(2), 926-957. [http://dx.doi.org/10.3390/cancers6020926]. [PMID: 24743778].
[8]
Fagard, R.; Metelev, V.; Souissi, I.; Baran-Marszak, F. STAT3 inhibitors for cancer therapy: Have all roads been explored? JAK-STAT, 2013, 2(1), e22882. [http://dx.doi.org/10.4161/jkst.22882]. [PMID: 24058788].
[9]
O’Shea, J.J.; Schwartz, D.M.; Villarino, A.V.; Gadina, M.; McInnes, I.B.; Laurence, A. The JAK-STAT pathway: Impact on human disease and therapeutic intervention. Annu. Rev. Med., 2015, 66(1), 311-328. [http://dx.doi.org/10.1146/annurev-med-051113-024537]. [PMID: 25587654].
[10]
Liongue, C.; Sertori, R.; Ward, A.C. Evolution of cytokine receptor signaling. J. Immunol., 2016, 197(1), 11-18. [http://dx.doi.org/10.4049/jimmunol.1600372]. [PMID: 27317733].
[11]
Yu, H.; Jove, R. The STATs of cancer--new molecular targets come of age. Nat. Rev. Cancer, 2004, 4(2), 97-105. [http://dx.doi.org/10.1038/nrc1275]. [PMID: 14964307].
[12]
Haura, E.B.; Turkson, J.; Jove, R. Mechanisms of disease: Insights into the emerging role of signal transducers and activators of transcription in cancer. Nat. Clin. Pract. Oncol., 2005, 2(6), 315-324. [http://dx.doi.org/10.1038/ncponc0195]. [PMID: 16264989].
[13]
Gao, Y.; Zhao, H.; Wang, P.; Wang, J.; Zou, L. The roles of SOCS3 and STAT3 in bacterial infection and inflammatory diseases. Scand. J. Immunol., 2018, 88(6), e12727. [http://dx.doi.org/10.1111/sji.12727]. [PMID: 30341772].
[14]
Groner, B.; von Manstein, V. Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition. Mol. Cell. Endocrinol., 2017, 451, 1-14. [http://dx.doi.org/10.1016/j.mce.2017.05.033]. [PMID: 28576744].
[15]
Wang, Y.; Shen, Y.; Wang, S.; Shen, Q.; Zhou, X. The role of STAT3 in leading the crosstalk between human cancers and the immune system. Cancer Lett., 2018, 415, 117-128. [http://dx.doi.org/10.1016/j.canlet.2017.12.003]. [PMID: 29222039].
[16]
Hirano, T.; Ishihara, K.; Hibi, M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene, 2000, 19(21), 2548-2556. [http://dx.doi.org/10.1038/sj.onc.1203551]. [PMID: 10851053].
[17]
Heinrich, P.C.; Behrmann, I.; Müller-Newen, G.; Schaper, F.; Graeve, L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem. J., 1998, 334(Pt 2), 297-314. [http://dx.doi.org/10.1042/bj3340297]. [PMID: 9716487].
[18]
Aigner, P.; Just, V.; Stoiber, D. STAT3 isoforms: Alternative fates in cancer? Cytokine, 2019, 118, 27-34. [PMID: 30031681].
[19]
Schaefer, T.S.; Sanders, L.K.; Nathans, D. Cooperative transcriptional activity of Jun and Stat3 beta, a short form of Stat3. Proc. Natl. Acad. Sci. USA, 1995, 92(20), 9097-9101. [http://dx.doi.org/10.1073/pnas.92.20.9097]. [PMID: 7568080].
[20]
Shao, H.; Quintero, A.J.; Tweardy, D.J. Identification and characterization of cis elements in the STAT3 gene regulating STAT3 alpha and STAT3 beta messenger RNA splicing. Blood, 2001, 98(13), 3853-3856. [http://dx.doi.org/10.1182/blood.V98.13.3853]. [PMID: 11739197].
[21]
Zhang, Y.; Wang, D.; Xu, J.; Wang, Y.; Ma, F.; Li, Z.; Liu, N. Stat3 activation is critical for pluripotency maintenance. J. Cell. Physiol., 2019, 234(2), 1044-1051. [http://dx.doi.org/10.1002/jcp.27241]. [PMID: 30256396].
[22]
Huang, G.; Yan, H.; Ye, S.; Tong, C.; Ying, Q.L. STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates mouse ESC fates. Stem Cells, 2014, 32(5), 1149-1160. [http://dx.doi.org/10.1002/stem.1609]. [PMID: 24302476].
[23]
Hazan-Halevy, I.; Harris, D.; Liu, Z.; Liu, J.; Li, P.; Chen, X.; Shanker, S.; Ferrajoli, A.; Keating, M.J.; Estrov, Z. STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood, 2010, 115(14), 2852-2863. [http://dx.doi.org/10.1182/blood-2009-10-230060]. [PMID: 20154216].
[24]
Shi, X.; Zhang, H.; Paddon, H.; Lee, G.; Cao, X.; Pelech, S. Phosphorylation of STAT3 serine-727 by cyclin-dependent kinase 1 is critical for nocodazole-induced mitotic arrest. Biochemistry, 2006, 45(18), 5857-5867. [http://dx.doi.org/10.1021/bi052490j]. [PMID: 16669628].
[25]
Qin, H.R.; Kim, H.J.; Kim, J.Y.; Hurt, E.M.; Klarmann, G.J.; Kawasaki, B.T.; Duhagon Serrat, M.A.; Farrar, W.L. Activation of Stat3 through a Phosphomimetic Serine727 promotes prostate tumorigenesis independent of tyrosine705 phosphorylation. Cancer Res., 2008, 68(19), 7736-7741. [http://dx.doi.org/10.1158/0008-5472.CAN-08-1125]. [PMID: 18829527].
[26]
Hendry, L.; John, S. Regulation of STAT signalling by proteolytic processing. Eur. J. Biochem., 2004, 271(23-24), 4613-4620. [http://dx.doi.org/10.1111/j.1432-1033.2004.04424.x]. [PMID: 15606748].
[27]
Hevehan, D.L.; Miller, W.M.; Papoutsakis, E.T. Differential expression and phosphorylation of distinct STAT3 proteins during granulocytic differentiation. Blood, 2002, 99(5), 1627-1637. [http://dx.doi.org/10.1182/blood.V99.5.1627]. [PMID: 11861277].
[28]
Caldenhoven, E.; van Dijk, T.B.; Solari, R.; Armstrong, J.; Raaijmakers, J.A.; Lammers, J.W.; Koenderman, L.; de Groot, R.P. STAT3β, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription. J. Biol. Chem., 1996, 271(22), 13221-13227. [http://dx.doi.org/10.1074/jbc.271.22.13221]. [PMID: 8675499].
[29]
Maritano, D.; Sugrue, M.L.; Tininini, S.; Dewilde, S.; Strobl, B.; Fu, X.; Murray-Tait, V.; Chiarle, R.; Poli, V. The STAT3 isoforms α and β have unique and specific functions. Nat. Immunol., 2004, 5(4), 401-409. [http://dx.doi.org/10.1038/ni1052]. [PMID: 15021879].
[30]
Ng, I.H.; Ng, D.C.; Jans, D.A.; Bogoyevitch, M.A. Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes. Biochem. J., 2012, 447(1), 125-136. [http://dx.doi.org/10.1042/BJ20120941]. [PMID: 22799634].
[31]
Schaefer, T.S.; Sanders, L.K.; Park, O.K.; Nathans, D. Functional differences between Stat3alpha and Stat3beta. Mol. Cell. Biol., 1997, 17(9), 5307-5316. [http://dx.doi.org/10.1128/MCB.17.9.5307]. [PMID: 9271408].
[32]
Park, O.K.; Schaefer, L.K.; Wang, W.; Schaefer, T.S. Dimer stability as a determinant of differential DNA binding activity of Stat3 isoforms. J. Biol. Chem., 2000, 275(41), 32244-32249. [http://dx.doi.org/10.1074/jbc.M005082200]. [PMID: 10915797].
[33]
Yoo, J.Y.; Huso, D.L.; Nathans, D.; Desiderio, S. Specific ablation of Stat3beta distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock. Cell, 2002, 108(3), 331-344. [http://dx.doi.org/10.1016/S0092-8674(02)00636-0]. [PMID: 11853668].
[34]
Alonzi, T.; Maritano, D.; Gorgoni, B.; Rizzuto, G.; Libert, C.; Poli, V. Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene activation in the liver. Mol. Cell. Biol., 2001, 21(5), 1621-1632. [http://dx.doi.org/10.1128/MCB.21.5.1621-1632.2001]. [PMID: 11238899].
[35]
Levy, D.E.; Darnell, J.E. Stats: Transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol., 2002, 3(9), 651-662. [http://dx.doi.org/10.1038/nrm909]. [PMID: 12209125].
[36]
Furqan, M.; Akinleye, A.; Mukhi, N.; Mittal, V.; Chen, Y.; Liu, D. STAT inhibitors for cancer therapy. J. Hematol. Oncol., 2013, 6(1), 90. [http://dx.doi.org/10.1186/1756-8722-6-90]. [PMID: 24308725].
[37]
Darnell, J.E.; Kerr, I.M.; Stark, G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 1994, 264(5164), 1415-1421. [http://dx.doi.org/10.1126/science.8197455]. [PMID: 8197455].
[38]
Zhong, Z.; Wen, Z.; Darnell, J.E. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science, 1994, 264(5155), 95-98. [http://dx.doi.org/10.1126/science.8140422]. [PMID: 8140422].
[39]
Khatib, H.; Huang, W.; Mikheil, D.; Schutzkus, V.; Monson, R.L. Effects of signal transducer and activator of transcription (STAT) genes STAT1 and STAT3 genotypic combinations on fertilization and embryonic survival rates in Holstein cattle. J. Dairy Sci., 2009, 92(12), 6186-6191. [http://dx.doi.org/10.3168/jds.2009-2439]. [PMID: 19923622].
[40]
Decker, T.; Kovarik, P. Transcription factor activity of STAT proteins: Structural requirements and regulation by phosphorylation and interacting proteins. Cell. Mol. Life Sci., 1999, 55(12), 1535-1546. [http://dx.doi.org/10.1007/s000180050393]. [PMID: 10526571].
[41]
Gupta, M.; Han, J.J.; Stenson, M.; Maurer, M.; Wellik, L.; Hu, G.; Ziesmer, S.; Dogan, A.; Witzig, T.E. Elevated serum IL-10 levels in diffuse large B-cell lymphoma: A mechanism of aberrant JAK2 activation. Blood, 2012, 119(12), 2844-2853. [http://dx.doi.org/10.1182/blood-2011-10-388538]. [PMID: 22323454].
[42]
Ernst, M.; Najdovska, M.; Grail, D.; Lundgren-May, T.; Buchert, M.; Tye, H.; Matthews, V.B.; Armes, J.; Bhathal, P.S.; Hughes, N.R.; Marcusson, E.G.; Karras, J.G.; Na, S.; Sedgwick, J.D.; Hertzog, P.J.; Jenkins, B.J. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J. Clin. Invest., 2008, 118(5), 1727-1738. [http://dx.doi.org/10.1172/JCI34944]. [PMID: 18431520].
[43]
Kunisada, K.; Hirota, H.; Fujio, Y.; Matsui, H.; Tani, Y.; Yamauchi-Takihara, K.; Kishimoto, T. Activation of JAK-STAT and MAP kinases by leukemia inhibitory factor through gp130 in cardiac myocytes. Circulation, 1996, 94(10), 2626-2632. [http://dx.doi.org/10.1161/01.CIR.94.10.2626]. [PMID: 8921810].
[44]
Zhao, D.; Pan, C.; Sun, J.; Gilbert, C.; Drews-Elger, K.; Azzam, D.J.; Picon-Ruiz, M.; Kim, M.; Ullmer, W.; El-Ashry, D.; Creighton, C.J.; Slingerland, J.M. VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2. Oncogene, 2015, 34(24), 3107-3119. [http://dx.doi.org/10.1038/onc.2014.257]. [PMID: 25151964].
[45]
Wang, Y.; van Boxel-Dezaire, A.H.; Cheon, H.; Yang, J.; Stark, G.R. STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proc. Natl. Acad. Sci. USA, 2013, 110(42), 16975-16980. [http://dx.doi.org/10.1073/pnas.1315862110]. [PMID: 24082147].
[46]
Zong, C.S.; Chan, J.; Levy, D.E.; Horvath, C.; Sadowski, H.B.; Wang, L.H. Mechanism of STAT3 activation by insulin-like growth factor I receptor. J. Biol. Chem., 2000, 275(20), 15099-15105. [http://dx.doi.org/10.1074/jbc.M000089200]. [PMID: 10747872].
[47]
Vignais, M.L.; Sadowski, H.B.; Watling, D.; Rogers, N.C.; Gilman, M. Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins. Mol. Cell. Biol., 1996, 16(4), 1759-1769. [http://dx.doi.org/10.1128/MCB.16.4.1759]. [PMID: 8657151].
[48]
Coppo, P.; Flamant, S.; De Mas, V.; Jarrier, P.; Guillier, M.; Bonnet, M.L.; Lacout, C.; Guilhot, F.; Vainchenker, W.; Turhan, A.G. BCR-ABL activates STAT3 via JAK and MEK pathways in human cells. Br. J. Haematol., 2006, 134(2), 171-179. [http://dx.doi.org/10.1111/j.1365-2141.2006.06161.x]. [PMID: 16846476].
[49]
Schreiner, S.J. Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. J. Biol. Chem., 2002, 277(47), 45680-45687. [DOI: 10.1074/jbc.M204255200].
[50]
Eyking, A.; Ey, B.; Rünzi, M.; Roig, A.I.; Reis, H.; Schmid, K.W.; Gerken, G.; Podolsky, D.K.; Cario, E. Toll-like receptor 4 variant D299G induces features of neoplastic progression in Caco-2 intestinal cells and is associated with advanced human colon cancer. Gastroenterology, 2011, 141(6), 2154-2165. [http://dx.doi.org/10.1053/j.gastro.2011.08.043]. [PMID: 21920464].
[51]
Lee, H.; Deng, J.; Kujawski, M.; Yang, C.; Liu, Y.; Herrmann, A.; Kortylewski, M.; Horne, D.; Somlo, G.; Forman, S.; Jove, R.; Yu, H. STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nat. Med., 2010, 16(12), 1421-1428. [http://dx.doi.org/10.1038/nm.2250]. [PMID: 21102457].
[52]
Chung, J.; Uchida, E.; Grammer, T.C.; Blenis, J. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol. Cell. Biol., 1997, 17(11), 6508-6516. [http://dx.doi.org/10.1128/MCB.17.11.6508]. [PMID: 9343414].
[53]
Lim, C.P.; Cao, X. Serine phosphorylation and negative regulation of Stat3 by JNK. J. Biol. Chem., 1999, 274(43), 31055-31061. [http://dx.doi.org/10.1074/jbc.274.43.31055]. [PMID: 10521505].
[54]
Jain, N.; Zhang, T.; Kee, W.H.; Li, W.; Cao, X. Protein kinase C delta associates with and phosphorylates Stat3 in an interleukin-6-dependent manner. J. Biol. Chem., 1999, 274(34), 24392-24400. [http://dx.doi.org/10.1074/jbc.274.34.24392]. [PMID: 10446219].
[55]
Androutsellis-Theotokis, A.; Leker, R.R.; Soldner, F.; Hoeppner, D.J.; Ravin, R.; Poser, S.W.; Rueger, M.A.; Bae, S.K.; Kittappa, R.; McKay, R.D. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature, 2006, 442(7104), 823-826. [http://dx.doi.org/10.1038/nature04940]. [PMID: 16799564].
[56]
Liu, H.; Ma, Y.; Cole, S.M.; Zander, C.; Chen, K.H.; Karras, J.; Pope, R.M. Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival. Blood, 2003, 102(1), 344-352. [http://dx.doi.org/10.1182/blood-2002-11-3396]. [PMID: 12637318].
[57]
Wegrzyn, J.; Potla, R.; Chwae, Y.J.; Zhang, Q.; Derecka, M.; Szczepanek, K. Szelag1, M.;Gornicka, A.;Moh, A.;Moghaddas, S.; Chen, Q.; Bobbili, S.;Fu, X.Y.; Lesnefsky, E.J. 372 A novel function of STAT3 in cellular respiration. Cytokine, 2008, 43(3), 331-331. [http://dx.doi.org/10.1016/j.cyto.2008.07.457].
[58]
Gough, D.J.; Corlett, A.; Schlessinger, K.; Wegrzyn, J.; Larner, A.C.; Levy, D.E. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science, 2009, 324(5935), 1713-1716. [http://dx.doi.org/10.1126/science.1171721]. [PMID: 19556508].
[59]
Butturini, E.; Gotte, G.; Dell’Orco, D.; Chiavegato, G.; Marino, V.; Canetti, D.; Cozzolino, F.; Monti, M.; Pucci, P.; Mariotto, S. Intermolecular disulfide bond influences unphosphorylated STAT3 dimerization and function. Biochem. J., 2016, 473(19), 3205-3219. [http://dx.doi.org/10.1042/BCJ20160294]. [PMID: 27486258].
[60]
Yang, J.; Chatterjee-Kishore, M.; Staugaitis, S.M.; Nguyen, H.; Schlessinger, K.; Levy, D.E.; Stark, G.R. Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res., 2005, 65(3), 939-947. [PMID: 15705894].
[61]
Yang, J.; Liao, X.; Agarwal, M.K.; Barnes, L.; Auron, P.E.; Stark, G.R. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev., 2007, 21(11), 1396-1408. [http://dx.doi.org/10.1101/gad.1553707]. [PMID: 17510282].
[62]
Yuan, Z.L.; Guan, Y.J.; Chatterjee, D.; Chin, Y.E. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science, 2005, 307(5707), 269-273. [http://dx.doi.org/10.1126/science.1105166]. [PMID: 15653507].
[63]
Zhang, Y.; Wang, D.; Xu, J.; Wang, Y.; Ma, F.; Li, Z.; Liu, N. Stat3 activation is critical for pluripotency maintenance. J. Cell. Physiol., 2019, 234(2), 1044-1051. [http://dx.doi.org/10.1002/jcp.27241]. [PMID: 30256396].
[64]
Aaronson, D.S.; Horvath, C.M. A road map for those who don’t know JAK-STAT. Science, 2002, 296(5573), 1653-1655. [http://dx.doi.org/10.1126/science.1071545]. [PMID: 12040185].
[65]
Johnson, D.E.; O’Keefe, R.A.; Grandis, J.R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol., 2018, 15(4), 234-248. [http://dx.doi.org/10.1038/nrclinonc.2018.8]. [PMID: 29405201].
[66]
Yu, H.; Pardoll, D.; Jove, R. STATs in cancer inflammation and immunity: A leading role for STAT3. Nat. Rev. Cancer, 2009, 9(11), 798-809. [http://dx.doi.org/10.1038/nrc2734]. [PMID: 19851315].
[67]
Kortylewski, M.; Yu, H. Role of Stat3 in suppressing anti-tumor immunity. Curr. Opin. Immunol., 2008, 20(2), 228-233. [http://dx.doi.org/10.1016/j.coi.2008.03.010]. [PMID: 18479894].
[68]
Baek, S.H.; Ko, J.H.; Lee, H.; Jung, J.; Kong, M.; Lee, J.W.; Lee, J.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; Lee, S.G.; Shim, B.S.; Sethi, G.; Kim, S.H.; Yang, W.M.; Um, J.Y.; Ahn, K.S. Resveratrol inhibits STAT3 signaling pathway through the induction of SOCS-1: Role in apoptosis induction and radiosensitization in head and neck tumor cells. Phytomedicine, 2016, 23(5), 566-577. [http://dx.doi.org/10.1016/j.phymed.2016.02.011]. [PMID: 27064016].
[69]
Herrmann, A.; Kortylewski, M.; Kujawski, M.; Zhang, C.; Reckamp, K.; Armstrong, B.; Wang, L.; Kowolik, C.; Deng, J.; Figlin, R.; Yu, H. Targeting Stat3 in the myeloid compartment drastically improves the in vivo antitumor functions of adoptively transferred T cells. Cancer Res., 2010, 70(19), 7455-7464. [http://dx.doi.org/10.1158/0008-5472.CAN-10-0736]. [PMID: 20841481].
[70]
Yang, C.L.; Liu, Y.Y.; Ma, Y.G.; Xue, Y.X.; Liu, D.G.; Ren, Y.; Liu, X.B.; Li, Y.; Li, Z. Curcumin blocks small cell lung cancer cells migration, invasion, angiogenesis, cell cycle and neoplasia through Janus kinase-STAT3 signalling pathway. PLoS One, 2012, 7(5), e37960. [http://dx.doi.org/10.1371/journal.pone.0037960]. [PMID: 22662257].
[71]
Vainchenker, W.; Constantinescu, S.N. JAK/STAT signaling in hematological malignancies. Oncogene, 2013, 32(21), 2601-2613. [http://dx.doi.org/10.1038/onc.2012.347]. [PMID: 22869151].
[72]
Couronné, L.; Scourzic, L.; Pilati, C.; Della Valle, V.; Duffourd, Y.; Solary, E.; Vainchenker, W.; Merlio, J.P.; Beylot-Barry, M.; Damm, F.; Stern, M.H.; Gaulard, P.; Lamant, L.; Delabesse, E.; Merle-Beral, H.; Nguyen-Khac, F.; Fontenay, M.; Tilly, H.; Bastard, C.; Zucman-Rossi, J.; Bernard, O.A.; Mercher, T. STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model. Haematologica, 2013, 98(11), 1748-1752. [http://dx.doi.org/10.3324/haematol.2013.085068]. [PMID: 23872306].
[73]
Groner, B.; Von Manstein, V. Jak Stat signaling and targeted inhibition. Mol. Cell. Endocrinol., 2017, 451, 1-14. [http://dx.doi.org/10.1016/j.mce.2017.05.033]. [PMID: 28576744].
[74]
Duan, S.; Tsai, Y.; Keng, P.; Chen, Y.; Lee, S.O.; Chen, Y. IL-6 signaling contributes to cisplatin resistance in non-small cell lung cancer via the up-regulation of anti-apoptotic and DNA repair associated molecules. Oncotarget, 2015, 6(29), 27651-27660. [http://dx.doi.org/10.18632/oncotarget.4753]. [PMID: 26313152].
[75]
Yang, C.H.; Chou, H.C.; Fu, Y.N.; Yeh, C.L.; Cheng, H.W.; Chang, I.C.; Liu, K.J.; Chang, G.C.; Tsai, T.F.; Tsai, S.F.; Liu, H.P.; Wu, Y.C.; Chen, Y.T.; Huang, S.F.; Chen, Y.R. EGFR over-expression in non-small cell lung cancers harboring EGFR mutations is associated with marked down-regulation of CD82. Biochim. Biophys. Acta, 2015, 1852(7), 1540-1549. [http://dx.doi.org/10.1016/j.bbadis.2015.04.020]. [PMID: 25912735].
[76]
Harada, D.; Takigawa, N.; Kiura, K. The role of STAT3 in non-small cell lung cancer. Cancers (Basel), 2014, 6(2), 708-722. [http://dx.doi.org/10.3390/cancers6020708]. [PMID: 24675568].
[77]
He, G.; Yu, G.Y.; Temkin, V.; Ogata, H.; Kuntzen, C.; Sakurai, T.; Sieghart, W.; Peck-Radosavljevic, M.; Leffert, H.L.; Karin, M. Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell, 2010, 17(3), 286-297. [http://dx.doi.org/10.1016/j.ccr.2009.12.048]. [PMID: 20227042].
[78]
He, G.; Karin, M. NF-κB and STAT3 - key players in liver inflammation and cancer. Cell Res., 2011, 21(1), 159-168. [http://dx.doi.org/10.1038/cr.2010.183]. [PMID: 21187858].
[79]
Calvisi, D.F.; Ladu, S.; Gorden, A.; Farina, M.; Conner, E.A.; Lee, J.S.; Factor, V.M.; Thorgeirsson, S.S. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology, 2006, 130(4), 1117-1128. [http://dx.doi.org/10.1053/j.gastro.2006.01.006]. [PMID: 16618406].
[80]
Wu, W.Y.; Li, J.; Wu, Z.S.; Zhang, C.L.; Meng, X.L. STAT3 activation in monocytes accelerates liver cancer progression. BMC Cancer, 2011, 11(1), 506-506. [http://dx.doi.org/10.1186/1471-2407-11-506]. [PMID: 22136659].
[81]
Park, J.H.; van Wyk, H.; McMillan, D.C.; Quinn, J.; Clark, J.; Roxburgh, C.S.; Horgan, P.G.; Edwards, J. Signal Transduction and Activator of Transcription-3 (STAT3) in Patients with Colorectal Cancer: Associations with the Phenotypic Features of the Tumor and Host. Clin. Cancer Res., 2017, 23(7), 1698-1709. [http://dx.doi.org/10.1158/1078-0432.CCR-16-1416]. [PMID: 27678454].
[82]
Lin, L.; Liu, A.; Peng, Z.; Lin, H.J.; Li, P.K.; Li, C.; Lin, J. STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res., 2011, 71(23), 7226-7237. [http://dx.doi.org/10.1158/0008-5472.CAN-10-4660]. [PMID: 21900397].
[83]
Chai, E.Z.P.; Shanmugam, M.K.; Arfuso, F.; Dharmarajan, A.; Wang, C.; Kumar, A.P.; Samy, R.P.; Lim, L.H.K.; Wang, L.; Goh, B.C.; Ahn, K.S.; Hui, K.M.; Sethi, G. Targeting transcription factor STAT3 for cancer prevention and therapy. Pharmacol. Ther., 2016, 162, 86-97. [http://dx.doi.org/10.1016/j.pharmthera.2015.10.004]. [PMID: 26478441].
[84]
Kim, J.E.; Patel, M.; Ruzevick, J.; Jackson, C.M.; Lim, M. STAT3 Activation in Glioblastoma: Biochemical and therapeutic implications. Cancers (Basel), 2014, 6(1), 376-395. [http://dx.doi.org/10.3390/cancers6010376]. [PMID: 24518612].
[85]
Akira, S.; Nishio, Y.; Inoue, M.; Wang, X.J.; Wei, S.; Matsusaka, T.; Yoshida, K.; Sudo, T.; Naruto, M.; Kishimoto, T. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell, 1994, 77(1), 63-71. [http://dx.doi.org/10.1016/0092-8674(94)90235-6]. [PMID: 7512451].
[86]
Mackey-Lawrence, N.M.; Petri, W.A., Jr Leptin and mucosal immunity. Mucosal Immunol., 2012, 5(5), 472-479. [http://dx.doi.org/10.1038/mi.2012.40]. [PMID: 22692456].
[87]
Sehgal, P.B. Paradigm shifts in the cell biology of STAT signaling. Semin. Cell Dev. Biol., 2008, 19(4), 329-340. [http://dx.doi.org/10.1016/j.semcdb.2008.07.003]. [PMID: 18691663].
[88]
Roca Suarez, A.A.; Van Renne, N.; Baumert, T.F.; Lupberger, J. Viral manipulation of STAT3: Evade, exploit, and injure. PLoS Pathog., 2018, 14(3), e1006839. [http://dx.doi.org/10.1371/journal.ppat.1006839]. [PMID: 29543893].
[89]
Liu, F.; Poursine-Laurent, J.; Wu, H.Y.; Link, D.C. Interleukin-6 and the granulocyte colony-stimulating factor receptor are major independent regulators of granulopoiesis in vivo but are not required for lineage commitment or terminal differentiation. Blood, 1997, 90(7), 2583-2590. [PMID: 9326224].
[90]
Rochman, I.; Paul, W.E.; Ben-Sasson, S.Z. IL-6 increases primed cell expansion and survival. J. Immunol., 2005, 174(8), 4761-4767. [http://dx.doi.org/10.4049/jimmunol.174.8.4761]. [PMID: 15814701].
[91]
Yu, C.R.; Dambuza, I.M.; Lee, Y.J.; Frank, G.M.; Egwuagu, C.E. STAT3 regulates proliferation and survival of CD8+ T cells: enhances effector responses to HSV-1 infection, and inhibits IL-10+ regulatory CD8+ T cells in autoimmune uveitis. Mediators Inflamm., 2013, 2013, 359674. [http://dx.doi.org/10.1155/2013/359674]. [PMID: 24204098].
[92]
Ivanov, I.I.; McKenzie, B.S.; Zhou, L.; Tadokoro, C.E.; Lepelley, A.; Lafaille, J.J.; Cua, D.J.; Littman, D.R. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell, 2006, 126(6), 1121-1133. [http://dx.doi.org/10.1016/j.cell.2006.07.035]. [PMID: 16990136].
[93]
Korn, T.; Mitsdoerffer, M.; Croxford, A.L.; Awasthi, A.; Dardalhon, V.A.; Galileos, G.; Vollmar, P.; Stritesky, G.L.; Kaplan, M.H.; Waisman, A.; Kuchroo, V.K.; Oukka, M. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc. Natl. Acad. Sci. USA, 2008, 105(47), 18460-18465. [http://dx.doi.org/10.1073/pnas.0809850105]. [PMID: 19015529].
[94]
Nowell, M.A.; Williams, A.S.; Carty, S.A.; Scheller, J.; Hayes, A.J.; Jones, G.W.; Richards, P.J.; Slinn, S.; Ernst, M.; Jenkins, B.J.; Topley, N.; Rose-John, S.; Jones, S.A. Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis. J. Immunol., 2009, 182(1), 613-622. [http://dx.doi.org/10.4049/jimmunol.182.1.613]. [PMID: 19109195].
[95]
Ma, C.S.; Avery, D.T.; Chan, A.; Batten, M.; Bustamante, J.; Boisson-Dupuis, S.; Arkwright, P.D.; Kreins, A.Y.; Averbuch, D.; Engelhard, D.; Magdorf, K.; Kilic, S.S.; Minegishi, Y.; Nonoyama, S.; French, M.A.; Choo, S.; Smart, J.M.; Peake, J.; Wong, M.; Gray, P.; Cook, M.C.; Fulcher, D.A.; Casanova, J.L.; Deenick, E.K.; Tangye, S.G. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood, 2012, 119(17), 3997-4008. [http://dx.doi.org/10.1182/blood-2011-11-392985]. [PMID: 22403255].
[96]
Eto, D.; Lao, C.; DiToro, D.; Barnett, B.; Escobar, T.C.; Kageyama, R.; Yusuf, I.; Crotty, S. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS One, 2011, 6(3), e17739. [http://dx.doi.org/10.1371/journal.pone.0017739]. [PMID: 21423809].
[97]
Ma, C.S.; Deenick, E.K.; Batten, M.; Tangye, S.G. The origins, function, and regulation of T follicular helper cells. J. Exp. Med., 2012, 209(7), 1241-1253. [http://dx.doi.org/10.1084/jem.20120994]. [PMID: 22753927].
[98]
Ouyang, W.; Rutz, S.; Crellin, N.K.; Valdez, P.A.; Hymowitz, S.G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol., 2011, 29(29), 71-109. [http://dx.doi.org/10.1146/annurev-immunol-031210-101312]. [PMID: 21166540].
[99]
Wu, C.; Orozco, C.; Boyer, J.; Leglise, M.; Goodale, J.; Batalov, S.; Hodge, C.L.; Haase, J.; Janes, J.; Huss, J.W., III; Su, A.I. BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol., 2009, 10(11), R130. [http://dx.doi.org/10.1186/gb-2009-10-11-r130]. [PMID: 19919682].
[100]
Cavani, A.; Nasorri, F.; Prezzi, C.; Sebastiani, S.; Albanesi, C.; Girolomoni, G. Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses. J. Invest. Dermatol., 2000, 114(2), 295-302. [http://dx.doi.org/10.1046/j.1523-1747.2000.00881.x]. [PMID: 10651989].
[101]
Itoh, K.; Hirohata, S. The role of IL-10 in human B cell activation, proliferation, and differentiation. J. Immunol., 1995, 154(9), 4341-4350. [PMID: 7722292].
[102]
Saito, M.; Nagasawa, M.; Takada, H.; Hara, T.; Tsuchiya, S.; Agematsu, K.; Yamada, M.; Kawamura, N.; Ariga, T.; Tsuge, I.; Nonoyama, S.; Karasuyama, H.; Minegishi, Y. Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells. J. Exp. Med., 2011, 208(2), 235-249. [http://dx.doi.org/10.1084/jem.20100799]. [PMID: 21300911].
[103]
Yoshimura, A.; Naka, T.; Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nat. Rev. Immunol., 2007, 7(6), 454-465. [http://dx.doi.org/10.1038/nri2093]. [PMID: 17525754].
[104]
Yu, H.; Lee, H.; Herrmann, A.; Buettner, R.; Jove, R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat. Rev. Cancer, 2014, 14(11), 736-746. [http://dx.doi.org/10.1038/nrc3818]. [PMID: 25342631].
[105]
Darnell, J.E. Validating Stat3 in cancer therapy. Nat. Med., 2005, 11(6), 595-596. [http://dx.doi.org/10.1038/nm0605-595]. [PMID: 15937466].
[106]
Resetca, D.; Haftchenary, S.; Gunning, P.T.; Wilson, D.J. Changes in signal transducer and activator of transcription 3 (STAT3) dynamics induced by complexation with pharmacological inhibitors of Src homology 2 (SH2) domain dimerization. J. Biol. Chem., 2014, 289(47), 32538-32547. [http://dx.doi.org/10.1074/jbc.M114.595454]. [PMID: 25288792].
[107]
Shin, D.S.; Kim, H.N.; Shin, K.D.; Yoon, Y.J.; Kim, S.J.; Han, D.C.; Kwon, B.M. Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells. Cancer Res., 2009, 69(1), 193-202. [http://dx.doi.org/10.1158/0008-5472.CAN-08-2575]. [PMID: 19118003].
[108]
Timofeeva, O.A.; Gaponenko, V.; Lockett, S.J.; Tarasov, S.G.; Jiang, S.; Michejda, C.J.; Perantoni, A.O.; Tarasova, N.I. Rationally designed inhibitors identify STAT3 N-domain as a promising anticancer drug target. ACS Chem. Biol., 2007, 2(12), 799-809. [http://dx.doi.org/10.1021/cb700186x]. [PMID: 18154267].
[109]
Liu, L.; McBride, K.M.; Reich, N.C. STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3. Proc. Natl. Acad. Sci. USA, 2005, 102(23), 8150-8155. [http://dx.doi.org/10.1073/pnas.0501643102]. [PMID: 15919823].
[110]
Nkansah, E.; Shah, R.; Collie, G.W.; Parkinson, G.N.; Palmer, J.; Rahman, K.M.; Bui, T.T.; Drake, A.F.; Husby, J.; Neidle, S.; Zinzalla, G.; Thurston, D.E.; Wilderspin, A.F. Observation of unphosphorylated STAT3 core protein binding to target dsDNA by PEMSA and X-ray crystallography. FEBS Lett., 2013, 587(7), 833-839. [http://dx.doi.org/10.1016/j.febslet.2013.01.065]. [PMID: 23434585].
[111]
Beebe, J.D.; Liu, J.Y.; Zhang, J.T. Two decades of research in discovery of anticancer drugs targeting STAT3, how close are we? Pharmacol. Ther., 2018, 191, 74-91. [http://dx.doi.org/10.1016/j.pharmthera.2018.06.006]. [PMID: 29933035].
[112]
Song, H.; Wang, R.; Wang, S.; Lin, J. A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. Proc. Natl. Acad. Sci. USA, 2005, 102(13), 4700-4705. [http://dx.doi.org/10.1073/pnas.0409894102]. [PMID: 15781862].
[113]
Chen, C.L.; Loy, A.; Cen, L.; Chan, C.; Hsieh, F.C.; Cheng, G.; Wu, B.; Qualman, S.J.; Kunisada, K.; Yamauchi-Takihara, K.; Lin, J. Signal transducer and activator of transcription 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells. BMC Cancer, 2007, 7(1), 111. [http://dx.doi.org/10.1186/1471-2407-7-111]. [PMID: 17598902].
[114]
Miyoshi, K.; Takaishi, M.; Nakajima, K.; Ikeda, M.; Kanda, T.; Tarutani, M.; Iiyama, T.; Asao, N.; DiGiovanni, J.; Sano, S. Stat3 as a therapeutic target for the treatment of psoriasis: a clinical feasibility study with STA-21, a Stat3 inhibitor. J. Invest. Dermatol., 2011, 131(1), 108-117. [http://dx.doi.org/10.1038/jid.2010.255]. [PMID: 20811392].
[115]
Nadeem, A.; Al-Harbi, N.O.; Ansari, M.A.; Al-Harbi, M.M.; El-Sherbeeny, A.M.; Zoheir, K.M.A.; Attia, S.M.; Hafez, M.M.; Al-Shabanah, O.A.; Ahmad, S.F. Psoriatic inflammation enhances allergic airway inflammation through IL-23/STAT3 signaling in a murine model. Biochem. Pharmacol., 2017, 124, 69-82. [http://dx.doi.org/10.1016/j.bcp.2016.10.012]. [PMID: 27984001].
[116]
Bhasin, D.; Cisek, K.; Pandharkar, T.; Regan, N.; Li, C.; Pandit, B.; Lin, J.; Li, P.K. Design, synthesis, and studies of small molecule STAT3 inhibitors. Bioorg. Med. Chem. Lett., 2008, 18(1), 391-395. [http://dx.doi.org/10.1016/j.bmcl.2007.10.031]. [PMID: 18006313].
[117]
Lin, L.; Hutzen, B.; Li, P.K.; Ball, S.; Zuo, M.; DeAngelis, S.; Foust, E.; Sobo, M.; Friedman, L.; Bhasin, D.; Cen, L.; Li, C.; Lin, J. A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells. Neoplasia, 2010, 12(1), 39-50. [http://dx.doi.org/10.1593/neo.91196]. [PMID: 20072652].
[118]
Ball, S.; Li, C.; Li, P.K.; Lin, J. The small molecule, LLL12, inhibits STAT3 phosphorylation and induces apoptosis in medulloblastoma and glioblastoma cells. PLoS One, 2011, 6(4), e18820. [http://dx.doi.org/10.1371/journal.pone.0018820]. [PMID: 21526200].
[119]
Lin, L.; Benson, D.M., Jr; DeAngelis, S.; Bakan, C.E.; Li, P.K.; Li, C.; Lin, J. A small molecule, LLL12 inhibits constitutive STAT3 and IL-6-induced STAT3 signaling and exhibits potent growth suppressive activity in human multiple myeloma cells. Int. J. Cancer, 2012, 130(6), 1459-1469. [http://dx.doi.org/10.1002/ijc.26152]. [PMID: 21520044].
[120]
Wei, C.C.; Ball, S.; Lin, L.; Liu, A.; Fuchs, J.R.; Li, P.K.; Li, C.; Lin, J. Two small molecule compounds, LLL12 and FLLL32, exhibit potent inhibitory activity on STAT3 in human rhabdomyosarcoma cells. Int. J. Oncol., 2011, 38(1), 279-285. [PMID: 21109950].
[121]
Onimoe, G.I.; Liu, A.; Lin, L.; Wei, C.C.; Schwartz, E.B.; Bhasin, D.; Li, C.; Fuchs, J.R.; Li, P.K.; Houghton, P.; Termuhlen, A.; Gross, T.; Lin, J. Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice. Invest. New Drugs, 2012, 30(3), 916-926. [http://dx.doi.org/10.1007/s10637-011-9645-1]. [PMID: 21340507].
[122]
Jung, K.H.; Yoo, W.; Stevenson, H.L.; Deshpande, D.; Shen, H.; Gagea, M.; Yoo, S.Y.; Wang, J.; Eckols, T.K.; Bharadwaj, U.; Tweardy, D.J. Multi-functional effects of a small-molecule STAT3 inhibitor on NASH and HCC in mice. Clin. Cancer Res., 2017, 23(18), 5537-5546. [http://dx.doi.org/10.1158/1078-0432.CCR-16-2253]. [PMID: 28533225].
[123]
Schust, J.; Sperl, B.; Hollis, A.; Mayer, T.U.; Berg, T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem. Biol., 2006, 13(11), 1235-1242. [http://dx.doi.org/10.1016/j.chembiol.2006.09.018]. [PMID: 17114005].
[124]
Adachi, M.; Cui, C.; Dodge, C.T.; Bhayani, M.K.; Lai, S.Y. Targeting STAT3 inhibits growth and enhances radiosensitivity in head and neck squamous cell carcinoma. Oral Oncol., 2012, 48(12), 1220-1226. [http://dx.doi.org/10.1016/j.oraloncology.2012.06.006]. [PMID: 22770899].
[125]
Villalva, C.; Martin-Lannerée, S.; Cortes, U.; Dkhissi, F.; Wager, M.; Le Corf, A.; Tourani, J.M.; Dusanter-Fourt, I.; Turhan, A.G.; Karayan-Tapon, L. STAT3 is essential for the maintenance of neurosphere-initiating tumor cells in patients with glioblastomas: a potential for targeted therapy? Int. J. Cancer, 2011, 128(4), 826-838. [http://dx.doi.org/10.1002/ijc.25416]. [PMID: 20473906].
[126]
Chung, S.S.; Giehl, N.; Wu, Y.; Vadgama, J.V. STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits. Int. J. Oncol., 2014, 44(2), 403-411. [http://dx.doi.org/10.3892/ijo.2013.2195]. [PMID: 24297508].
[127]
Han, Z.; Wang, X.; Ma, L.; Chen, L.; Xiao, M.; Huang, L.; Cao, Y.; Bai, J.; Ma, D.; Zhou, J.; Hong, Z. Inhibition of STAT3 signaling targets both tumor-initiating and differentiated cell populations in prostate cancer. Oncotarget, 2014, 5(18), 8416-8428. [http://dx.doi.org/10.18632/oncotarget.2314]. [PMID: 25261365].
[128]
Lin, L.; Hutzen, B.; Lee, H.F.; Peng, Z.; Wang, W.; Zhao, C.; Lin, H.J.; Sun, D.; Li, P.K.; Li, C.; Korkaya, H.; Wicha, M.S.; Lin, J. Evaluation of STAT3 signaling in ALDH+ and ALDH+/CD44+/CD24- subpopulations of breast cancer cells. PLoS One, 2013, 8(12), e82821. [http://dx.doi.org/10.1371/journal.pone.0082821]. [PMID: 24376586].
[129]
Pan, Y.; Zhou, F.; Zhang, R.; Claret, F.X. Stat3 inhibitor Stattic exhibits potent antitumor activity and induces chemo- and radio-sensitivity in nasopharyngeal carcinoma. PLoS One, 2013, 8(1), e54565. [http://dx.doi.org/10.1371/journal.pone.0054565]. [PMID: 23382914].
[130]
Matsuno, K.; Masuda, Y.; Uehara, Y.; Sato, H.; Muroya, A.; Takahashi, O.; Yokotagawa, T.; Furuya, T.; Okawara, T.; Otsuka, M.; Ogo, N.; Ashizawa, T.; Oshita, C.; Tai, S.; Ishii, H.; Akiyama, Y.; Asai, A. Identification of a new series of STAT3 inhibitors by virtual screening. ACS Med. Chem. Lett., 2010, 1(8), 371-375. [http://dx.doi.org/10.1021/ml1000273]. [PMID: 24900220].
[131]
Ashizawa, T.; Miyata, H.; Ishii, H.; Oshita, C.; Matsuno, K.; Masuda, Y.; Furuya, T.; Okawara, T.; Otsuka, M.; Ogo, N.; Asai, A.; Akiyama, Y. Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation. Int. J. Oncol., 2011, 38(5), 1245-1252. [PMID: 21369699].
[132]
Siddiquee, K.; Zhang, S.; Guida, W.C.; Blaskovich, M.A.; Greedy, B.; Lawrence, H.R.; Yip, M.L.; Jove, R.; McLaughlin, M.M.; Lawrence, N.J.; Sebti, S.M.; Turkson, J. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc. Natl. Acad. Sci. USA, 2007, 104(18), 7391-7396. [http://dx.doi.org/10.1073/pnas.0609757104]. [PMID: 17463090].
[133]
Bu, L.L.; Deng, W.W.; Huang, C.F.; Liu, B.; Zhang, W.F.; Sun, Z.J. Inhibition of STAT3 reduces proliferation and invasion in salivary gland adenoid cystic carcinoma. Am. J. Cancer Res., 2015, 5(5), 1751-1761. [PMID: 26175943].
[134]
Chen, C.L.; Loy, A.; Cen, L.; Chan, C.; Hsieh, F.C.; Cheng, G.; Wu, B.; Qualman, S.J.; Kunisada, K.; Yamauchi-Takihara, K.; Lin, J. Signal transducer and activator of transcription 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells. BMC Cancer, 2007, 7(1), 111. [http://dx.doi.org/10.1186/1471-2407-7-111]. [PMID: 17598902].
[135]
Bu, L.L.; Zhao, Z.L.; Liu, J.F.; Ma, S.R.; Huang, C.F.; Liu, B.; Zhang, W.F.; Sun, Z.J. STAT3 blockade enhances the efficacy of conventional chemotherapeutic agents by eradicating head neck stemloid cancer cell. Oncotarget, 2015, 6(39), 41944-41958. [http://dx.doi.org/10.18632/oncotarget.5986]. [PMID: 26556875].
[136]
Kortylewski, M.; Yu, H. Stat3 as a potential target for cancer immunotherapy. J. Immunother., 2007, 30(2), 131-139. [http://dx.doi.org/10.1097/01.cji.0000211327.76266.65]. [PMID: 17471161].
[137]
Lin, L.; Amin, R.; Gallicano, G.I.; Glasgow, E.; Jogunoori, W.; Jessup, J.M.; Zasloff, M.; Marshall, J.L.; Shetty, K.; Johnson, L.; Mishra, L.; He, A.R. The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling. Oncogene, 2009, 28(7), 961-972. [http://dx.doi.org/10.1038/onc.2008.448]. [PMID: 19137011].
[138]
Zhang, X.; Yue, P.; Fletcher, S.; Zhao, W.; Gunning, P.T.; Turkson, J. A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes. Biochem. Pharmacol., 2010, 79(10), 1398-1409. [http://dx.doi.org/10.1016/j.bcp.2010.01.001]. [PMID: 20067773].
[139]
Fletcher, S.; Singh, J.; Zhang, X.; Yue, P.; Page, B.D.; Sharmeen, S.; Shahani, V.M.; Zhao, W.; Schimmer, A.D.; Turkson, J.; Gunning, P.T. Disruption of transcriptionally active Stat3 dimers with non-phosphorylated, salicylic acid-based small molecules: Potent in vitro and tumor cell activities. ChemBioChem, 2009, 10(12), 1959-1964. [http://dx.doi.org/10.1002/cbic.200900172]. [PMID: 19644994].
[140]
Page, B.D.; Fletcher, S.; Yue, P.; Li, Z.; Zhang, X.; Sharmeen, S.; Datti, A.; Wrana, J.L.; Trudel, S.; Schimmer, A.D.; Turkson, J.; Gunning, P.T. Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain. Bioorg. Med. Chem. Lett., 2011, 21(18), 5605-5609. [http://dx.doi.org/10.1016/j.bmcl.2011.06.056]. [PMID: 21788134].
[141]
Urlam, M.K.; Pireddu, R.; Ge, Y.; Zhang, X.; Sun, Y.; Lawrence, H.R.; Guida, W.C.; Sebti, S.M.; Lawrence, N.J. Development of new N-arylbenzamides as STAT3 dimerization inhibitors. MedChemComm, 2013, 4(6), 932-941. [http://dx.doi.org/10.1039/c3md20323a]. [PMID: 24073326].
[142]
Huang, W.; Dong, Z.; Wang, F.; Peng, H.; Liu, J.Y.; Zhang, J.T. A small molecule compound targeting STAT3 DNA-binding domain inhibits cancer cell proliferation, migration, and invasion. ACS Chem. Biol., 2014, 9(5), 1188-1196. [http://dx.doi.org/10.1021/cb500071v]. [PMID: 24661007].
[143]
Huang, W.; Dong, Z.; Chen, Y.; Wang, F.; Wang, C.J.; Peng, H.; He, Y.; Hangoc, G.; Pollok, K.; Sandusky, G.; Fu, X.Y.; Broxmeyer, H.E.; Zhang, Z.Y.; Liu, J.Y.; Zhang, J.T. Small-molecule inhibitors targeting the DNA-binding domain of STAT3 suppress tumor growth, metastasis and STAT3 target gene expression in vivo. Oncogene, 2016, 35(6), 802. [http://dx.doi.org/10.1038/onc.2015.419]. [PMID: 26865226].
[144]
Cafferkey, C.; Chau, I. Novel STAT 3 inhibitors for treating gastric cancer. Expert Opin. Investig. Drugs, 2016, 25(9), 1023-1031. [http://dx.doi.org/10.1080/13543784.2016.1195807]. [PMID: 27322026].
[145]
Ren, X.; Duan, L.; He, Q.; Zhang, Z.; Zhou, Y.; Wu, D.; Pan, J.; Pei, D.; Ding, K. Identification of Niclosamide as a new small-molecule inhibitor of the STAT3 signaling pathway. ACS Med. Chem. Lett., 2010, 1(9), 454-459. [http://dx.doi.org/10.1021/ml100146z]. [PMID: 24900231].
[146]
Chen, H.; Yang, Z.; Ding, C.; Chu, L.; Zhang, Y.; Terry, K.; Liu, H.; Shen, Q.; Zhou, J. Discovery of O-Alkylamino tethered niclosamide derivatives as potent and orally bioavailable anticancer agents. ACS Med. Chem. Lett., 2013, 4(2), 180-185. [http://dx.doi.org/10.1021/ml3003082]. [PMID: 23459613].
[147]
Chen, H.; Yang, Z.; Ding, C.; Chu, L.; Zhang, Y.; Terry, K.; Liu, H.; Shen, Q.; Zhou, J. Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy. [J] Eur. J. Med. Chem., 2013, 62, 498-507. [http://dx.doi.org/10.1016/j.ejmech.2013.01.023]. [PMID: 23416191].
[148]
Chen, H.; Yang, Z.; Ding, C.; Xiong, A.; Wild, C.; Wang, L.; Ye, N.; Cai, G.; Flores, R.M.; Ding, Y.; Shen, Q.; Zhou, J. Discovery of potent anticancer agent HJC0416, an orally bioavailable small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3). Eur. J. Med. Chem., 2014, 82, 195-203. [http://dx.doi.org/10.1016/j.ejmech.2014.05.049]. [PMID: 24904966].
[149]
Shahani, V.M.; Yue, P.; Haftchenary, S.; Zhao, W.; Lukkarila, J.L.; Zhang, X.; Ball, D.; Nona, C.; Gunning, P.T.; Turkson, J. Identification of purine-scaffold small-molecule inhibitors of stat3 activation by QSAR studies. ACS Med. Chem. Lett., 2011, 2(1), 79-84. [http://dx.doi.org/10.1021/ml100224d]. [PMID: 21243039].
[150]
Yu, W.; Xiao, H.; Lin, J.; Li, C. Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design. J. Med. Chem., 2013, 56(11), 4402-4412. [http://dx.doi.org/10.1021/jm400080c]. [PMID: 23651330].
[151]
Li, H.; Liu, A.; Zhao, Z.; Xu, Y.; Lin, J.; Jou, D.; Li, C. Fragment-based drug design and drug repositioning using multiple ligand simultaneous docking (MLSD): identifying celecoxib and template compounds as novel inhibitors of signal transducer and activator of transcription 3 (STAT3). J. Med. Chem., 2011, 54(15), 5592-5596. [http://dx.doi.org/10.1021/jm101330h]. [PMID: 21678971].


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 15
Year: 2019
Page: [1305 - 1317]
Pages: 13
DOI: 10.2174/1568026619666190620145052
Price: $58

Article Metrics

PDF: 15
HTML: 2
EPUB: 1
PRC: 1