Transcription factor STAT3 as a novel molecular target for cancer prevention

Cancers

Volumn 6, Issue 2, 2014, Pages 926-957

  Xiong, Ailian ^a   Yang, Zhengduo ^a   Shen, Yicheng ^b   Zhou, Jia ^c   Shen, Qiang ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b University of Texas at Austin   (United States)

^c University of Texas Medical Branch School of Medicine   (United States)

Author keywords

Cancer prevention; STAT3; STAT3 inhibitors; Transcription factors

Indexed keywords

4 (3 BROMOANILINO) 6,7 DIMETHOXYQUINAZOLINE; 4 AMINO 7 TERT BUTYL 5 (4 CHLOROPHENYL)PYRAZOLO[3,4 D]PYRIMIDINE; 5 CHLORO N2 [1 (5 FLUORO 2 PYRIMIDINYL)ETHYL] N4 (5 METHYL 1H PYRAZOL 3 YL) 2,4 PYRIMIDINEDIAMINE; BENZYL ISOTHIOCYANATE; BP 1 102; BREVILIN A; CELECOXIB; CRYPTOTANSHINONE; CURCUMIN; CYTOKINE; DASATINIB; DBD 1; HJC 0123; HJC 0152; INTERLEUKIN 6; IS 3 295; JANUS KINASE; MITOPODOZIDE; N BENZYL 2 CYANO 3 (3,4 DIHYDROXYPHENYL)ACRYLAMIDE; N TERT BUTYL 3 [5 METHYL 2 [4 (4 METHYL 1 PIPERAZINYL)PHENYLAMINO] 4 PYRIMIDINYLAMINO]BENZENESULFONAMIDE; PROTEIN INHIBITOR; PROTEIN TYROSINE KINASE; S 31 1757; S 31 201; S 31 M 2001; SARACATINIB; STA 21; STAT3 PROTEIN; UNCLASSIFIED DRUG; XANTHOHUMOL;

ACUTE GRANULOCYTIC LEUKEMIA; AMINO TERMINAL SEQUENCE; APOPTOSIS; BREAST CANCER; CANCER PREVENTION; CANCER STEM CELL; CARCINOGENESIS; CELL DIFFERENTIATION; CELL MATURATION; CELL PROLIFERATION; CELL SURVIVAL; COLON TUMOR; DOWN REGULATION; DRUG BIOAVAILABILITY; DRUG DESIGN; EARLY CANCER; EMBRYONIC STEM CELL; GLIOMA; HUMAN; IMMUNE RESPONSE; INTESTINE CANCER; LIVER CELL CARCINOMA; LUNG CANCER; LUNG NON SMALL CELL CANCER; MALIGNANT NEOPLASTIC DISEASE; MALIGNANT TRANSFORMATION; MELANOMA; MOLECULARLY TARGETED THERAPY; MULTIPLE MYELOMA; MYELOMA; NEUROBLASTOMA; NONHUMAN; PANCREAS CANCER; PROSTATE CANCER; PROTEIN DNA BINDING; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; REVIEW; RHABDOMYOSARCOMA; SARCOMA; SIGNAL TRANSDUCTION; SYNOVIAL SARCOMA; TUMOR ESCAPE; TUMOR VASCULARIZATION; UPREGULATION;

EID: 84898909914     PISSN: None     EISSN: 20726694     Source Type: Journal    
DOI: 10.3390/cancers6020926     Document Type: Review

References (204)

1. Darnell, J.E., Jr.; Kerr, I.M.; Stark, G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994, 264, 1415-1421.
2. Ihle, J.N. The Stat family in cytokine signaling. Curr. Opin. Cell Biol. 2001, 13, 211-217.
3. Dimberg, L.Y.; Dimberg, A.; Ivarsson, K.; Fryknas, M.; Rickardson, L.; Tobin, G.; Ekman, S.; Larsson, R.; Gullberg, U.; Nilsson, K. et al. Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma. BMC Cancer 2012, 12, 318.
4. Grandis, J.R.; Drenning, S.D.; Chakraborty, A.; Zhou, M.Y.; Zeng, Q.; Pitt, A.S.; Tweardy, D.J. Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth In vitro. J. Clin. Investig. 1998, 102, 1385-1392.
5. Rane, S.G.; Reddy, E.P. Janus kinases: Components of multiple signaling pathways. Oncogene 2000, 19, 5662-5679.
6. 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, 63-71.
7. Choi, J.Y.; Li, W.L.; Kouri, R.E.; Yu, J.; Kao, F.T.; Ruano, G. Assignment of the acute phase response factor (APRF) gene to 17q21 by microdissection clone sequencing and fluorescence in situ hybridization of a P1 clone. Genomics 1996, 37, 264-265.
8. Yu, H.; Jove, R. The STATs of cancer-New molecular targets come of age. Nat. Rev. Cancer 2004, 4, 97-105.
9. Darnell, J.E., Jr. Transcription factors as targets for cancer therapy. Nat. Rev. Cancer 2002, 2, 740-749.
10. Yuan, Z.L.; Guan, Y.J.; Wang, L.; Wei, W.; Kane, A.B.; Chin, Y.E. Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells. Mol. Cell Biol. 2004, 24, 9390-9400.
11. Silva, C.M. Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene 2004, 23, 8017-8023.
12. Frank, D.A.; Mahajan, S.; Ritz, J. Blymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. J. Clin. Investig. 1997, 100, 3140-3148.
13. Wen, Z.; Zhong, Z.; Darnell, J.E., Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 1995, 82, 241-250.
14. Wen, Z.; Darnell, J.E., Jr. Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3. Nucleic Acids Res. 1997, 25, 2062-2067.
15. 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, 2852-2863.
16. Lim, C.P.; Cao, X. Serine phosphorylation and negative regulation of Stat3 by JNK. J. Biol. Chem. 1999, 274, 31055-31061.
17. 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, 6508-6516.
18. Zhang, W.; Chan, R.J.; Chen, H.; Yang, Z.; He, Y.; Zhang, X.; Luo, Y.; Yin, F.; Moh, A.; Miller, L.C. et al. Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia. J. Biol. Chem. 2009, 284, 22353-22363.
19. Hong, F.; Jaruga, B.; Kim, W.H.; Radaeva, S.; El-Assal, O.N.; Tian, Z.; Nguyen, V.A.; Gao, B. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: Regulation by SOCS. J. Clin. Investig. 2002, 110, 1503-1513.
20. Flowers, L.O.; Subramaniam, P.S.; Johnson, H.M. A SOCS-1 peptide mimetic inhibits both constitutive and IL-6 induced activation of STAT3 in prostate cancer cells. Oncogene 2005, 24, 2114-2120.
21. Groner, B.; Lucks, P.; Borghouts, C. The function of Stat3 in tumor cells and their microenvironment. Semin. Cell Dev. Biol. 2008, 19, 341-350.
22. 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, 8150-8155.
23. Gronowski, A.M.; Zhong, Z.; Wen, Z.; Thomas, M.J.; Darnell, J.E., Jr.; Rotwein, P. In vivo growth hormone treatment rapidly stimulates the tyrosine phosphorylation and activation of Stat3. Mol. Endocrinol. 1995, 9, 171-177.
24. Campbell, G.S.; Meyer, D.J.; Raz, R.; Levy, D.E.; Schwartz, J.; Carter-Su, C. Activation of acute phase response factor (APRF)/Stat3 transcription factor by growth hormone. J. Biol. Chem. 1995, 270, 3974-3979.
25. Zhang, S.S.; Liu, M.G.; Kano, A.; Zhang, C.; Fu, X.Y.; Barnstable, C.J. STAT3 activation in response to growth factors or cytokines participates in retina precursor proliferation. Exp. Eye Res. 2005, 81, 103-115.
26. Hilfiker-Kleiner, D.; Limbourg, A.; Drexler, H. STAT3-mediated activation of myocardial capillary growth. Trends Cardiovasc. Med. 2005, 15, 152-157.
27. Fukada, T.; Hibi, M.; Yamanaka, Y.; Takahashi-Tezuka, M.; Fujitani, Y.; Yamaguchi, T.; Nakajima, K.; Hirano, T. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: Involvement of STAT3 in anti-apoptosis. Immunity 1996, 5, 449-460.
28. Daino, H.; Matsumura, I.; Takada, K.; Odajima, J.; Tanaka, H.; Ueda, S.; Shibayama, H.; Ikeda, H.; Hibi, M.; Machii, T. et al. Induction of apoptosis by extracellular ubiquitin in human hematopoietic cells: Possible involvement of STAT3 degradation by proteasome pathway in interleukin 6-dependent hematopoietic cells. Blood 2000, 95, 2577-2585.
29. Epling-Burnette, P.K.; Liu, J.H.; Catlett-Falcone, R.; Turkson, J.; Oshiro, M.; Kothapalli, R.; Li, Y.; Wang, J.M.; Yang-Yen, H.F.; Karras, J. et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J. Clin. Investig. 2001, 107, 351-362.
30. Shirogane, T.; Fukada, T.; Muller, J.M.; Shima, D.T.; Hibi, M.; Hirano, T. Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity 1999, 11, 709-719.
31. Yang, Y.; Xu, Y.; Li, W.; Wang, G.; Song, Y.; Yang, G.; Han, X.; Du, Z.; Sun, L.; Ma, K. STAT3 induces muscle stem cell differentiation by interaction with myoD. Cytokine 2009, 46, 137-141.
32. Wang, K.; Wang, C.; Xiao, F.; Wang, H.; Wu, Z. JAK2/STAT2/STAT3 are required for myogenic differentiation. J. Biol. Chem. 2008, 283, 34029-34036.
33. Yanagisawa, M.; Nakashima, K.; Arakawa, H.; Ikenaka, K.; Yoshida, K.; Kishimoto, T.; Hisatsune, T.; Taga, T. Astrocyte differentiation of fetal neuroepithelial cells by interleukin-11 via activation of a common cytokine signal transducer, gp130, and a transcription factor, STAT3. J. Neurochem. 2000, 74, 1498-1504.
34. Lee, S.; Shen, R.; Cho, H.H.; Kwon, R.J.; Seo, S.Y.; Lee, J.W.; Lee, S.K. STAT3 promotes motor neuron differentiation by collaborating with motor neuron-specific LIM complex. Proc. Natl. Acad. Sci. USA 2013, 110, 11445-11450.
35. Itoh, S.; Udagawa, N.; Takahashi, N.; Yoshitake, F.; Narita, H.; Ebisu, S.; Ishihara, K. A critical role for interleukin-6 family-mediated Stat3 activation in osteoblast differentiation and bone formation. Bone 2006, 39, 505-512.
36. Wu, R.; Sun, S.; Steinberg, B.M. Requirement of STAT3 activation for differentiation of mucosal stratified squamous epithelium. Mol. Med. 2003, 9, 77-84.
37. Darnell, J.E., Jr. STATs and gene regulation. Science 1997, 277, 1630-1635.
38. Ernst, M.; Novak, U.; Nicholson, S.E.; Layton, J.E.; Dunn, A.R. The carboxyl-terminal domains of gp130-related cytokine receptors are necessary for suppressing embryonic stem cell differentiation. Involvement of STAT3. J. Biol. Chem. 1999, 274, 9729-9737.
39. Suzuki, R.; Sakamoto, H.; Yasukawa, H.; Masuhara, M.; Wakioka, T.; Sasaki, A.; Yuge, K.; Komiya, S.; Inoue, A.; Yoshimura, A. CIS3 and JAB have different regulatory roles in interleukin-6 mediated differentiation and STAT3 activation in M1 leukemia cells. Oncogene 1998, 17, 2271-2278.
40. Tomida, M.; Heike, T.; Yokota, T. Cytoplasmic domains of the leukemia inhibitory factor receptor required for STAT3 activation, differentiation, and growth arrest of myeloid leukemic cells. Blood 1999, 93, 1934-1941.
41. Chakraborty, A.; Tweardy, D.J. Stat3 and G-CSF-induced myeloid differentiation. Leuk. Lymphoma 1998, 30, 433-442.
42. Shimozaki, K.; Nakajima, K.; Hirano, T.; Nagata, S. Involvement of STAT3 in the granulocyte colony-stimulating factor-induced differentiation of myeloid cells. J. Biol. Chem. 1997, 272, 25184-25189.
43. 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, 2548-2556.
44. Park, S.J.; Nakagawa, T.; Kitamura, H.; Atsumi, T.; Kamon, H.; Sawa, S.; Kamimura, D.; Ueda, N.; Iwakura, Y.; Ishihara, K. et al. IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J. Immunol. 2004, 173, 3844-3854.
45. Rajasingh, J.; Bord, E.; Hamada, H.; Lambers, E.; Qin, G.; Losordo, D.W.; Kishore, R. STAT3-dependent mouse embryonic stem cell differentiation into cardiomyocytes: Analysis of molecular signaling and therapeutic efficacy of cardiomyocyte precommitted mES transplantation in a mouse model of myocardial infarction. Circ. Res. 2007, 101, 910-918.
46. You, W.; Tang, Q.; Zhang, C.; Wu, J.; Gu, C.; Wu, Z.; Li, X. IL-26 promotes the proliferation and survival of human gastric cancer cells by regulating the balance of STAT1 and STAT3 activation. PLoS One 2013, 8, e63588.
47. Liu, Y.; Lv, L.; Xiao, W.; Gong, C.; Yin, J.; Wang, D.; Sheng, H. Leptin activates STAT3 and ERK1/2 pathways and induces endometrial cancer cell proliferation. J. Huazhong. Univ. Sci. Technolog. Med. Sci. 2011, 31, 365-370.
48. Chen, R.J.; Ho, Y.S.; Guo, H.R.; Wang, Y.J. Rapid activation of Stat3 and ERK1/2 by nicotine modulates cell proliferation in human bladder cancer cells. Toxicol. Sci. 2008, 104, 283-293.
49. Corvinus, F.M.; Orth, C.; Moriggl, R.; Tsareva, S.A.; Wagner, S.; Pfitzner, E.B.; Baus, D.; Kaufmann, R.; Huber, L.A.; Zatloukal, K. et al. Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia 2005, 7, 545-555.
50. Horiguchi, A.; Oya, M.; Marumo, K.; Murai, M. STAT3, but not ERKs, mediates the IL-6-induced proliferation of renal cancer cells, ACHN and 769P. Kidney Int. 2002, 61, 926-938.
51. Zhang, Y.; Du, X.L.; Wang, C.J.; Lin, D.C.; Ruan, X.; Feng, Y.B.; Huo, Y.Q.; Peng, H.; Cui, J.L.; Zhang, T.T. et al. Reciprocal activation between PLK1 and Stat3 contributes to survival and proliferation of esophageal cancer cells. Gastroenterology 2012, 142, 521.e3-530.e3.
52. 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, 7226-7237.
53. Zhao, G.; Zhang, J.G.; Shi, Y.; Qin, Q.; Liu, Y.; Wang, B.; Tian, K.; Deng, S.C.; Li, X.; Zhu, S. et al. MiR-130b is a prognostic marker and inhibits cell proliferation and invasion in pancreatic cancer through targeting STAT3. PLoS One 2013, 8, e73803.
54. 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, 180-185.
55. 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. Eur. J. Med. Chem. 2013, 62, 498-507.
56. Lin, W.; Zheng, L.; Zhuang, Q.; Zhao, J.; Cao, Z.; Zeng, J.; Lin, S.; Xu, W.; Peng, J. Spica prunellae promotes cancer cell apoptosis, inhibits cell proliferation and tumor angiogenesis in a mouse model of colorectal cancer via suppression of stat3 pathway. BMC Complement. Altern. Med. 2013, 13, 144.
57. Zhuang, Q.; Hong, F.; Shen, A.; Zheng, L.; Zeng, J.; Lin, W.; Chen, Y.; Sferra, T.J.; Hong, Z.; Peng, J. Pien Tze Huang inhibits tumor cell proliferation and promotes apoptosis via suppressing the STAT3 pathway in a colorectal cancer mouse model. Int. J. Oncol. 2012, 40, 1569-1574.
58. Kanai, M.; Konda, Y.; Nakajima, T.; Izumi, Y.; Kanda, N.; Nanakin, A.; Kubohara, Y.; Chiba, T. Differentiation-inducing factor-1 (DIF-1) inhibits STAT3 activity involved in gastric cancer cell proliferation via MEK-ERK-dependent pathway. Oncogene 2003, 22, 548-554.
59. Pancotti, F.; Roncuzzi, L.; Maggiolini, M.; Gasperi-Campani, A. Caveolin-1 silencing arrests the proliferation of metastatic lung cancer cells through the inhibition of STAT3 signaling. Cell. Signal. 2012, 24, 1390-1397.
60. Bergers, G.; Benjamin, L.E. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer 2003, 3, 401-410.
61. McDougall, S.R.; Anderson, A.R.; Chaplain, M.A. Mathematical modelling of dynamic adaptive tumour-induced angiogenesis: Clinical implications and therapeutic targeting strategies. J. Theor. Biol. 2006, 241, 564-589.
62. Kalluri, R. Basement membranes: Structure, assembly and role in tumour angiogenesis. Nat. Rev. Cancer 2003, 3, 422-433.
63. Kang, S.H.; Yu, M.O.; Park, K.J.; Chi, S.G.; Park, D.H.; Chung, Y.G. Activated STAT3 regulates hypoxia-induced angiogenesis and cell migration in human glioblastoma. Neurosurgery 2010, 67, 1386-1395.
64. Niu, G.; Wright, K.L.; Huang, M.; Song, L.; Haura, E.; Turkson, J.; Zhang, S.; Wang, T.; Sinibaldi, D.; Coppola, D. et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002, 21, 2000-2008.
65. Kujawski, M.; Kortylewski, M.; Lee, H.; Herrmann, A.; Kay, H.; Yu, H. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J. Clin. Investig. 2008, 118, 3367-3377.
66. Jee, S.H.; Chu, C.Y.; Chiu, H.C.; Huang, Y.L.; Tsai, W.L.; Liao, Y.H.; Kuo, M.L. Interleukin-6 induced basic fibroblast growth factor-dependent angiogenesis in basal cell carcinoma cell line via JAK/STAT3 and PI3-kinase/Akt pathways. J. Investig. Dermatol. 2004, 123, 1169-1175.
67. Wei, D.; Le, X.; Zheng, L.; Wang, L.; Frey, J.A.; Gao, A.C.; Peng, Z.; Huang, S.; Xiong, H.Q.; Abbruzzese, J.L. et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 2003, 22, 319-329.
68. Wang, T.; Niu, G.; Kortylewski, M.; Burdelya, L.; Shain, K.; Zhang, S.; Bhattacharya, R.; Gabrilovich, D.; Heller, R.; Coppola, D. et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat. Med. 2004, 10, 48-54.
69. Saudemont, A.; Jouy, N.; Hetuin, D.; Quesnel, B. NK cells that are activated by CXCL10 can kill dormant tumor cells that resist CTL-mediated lysis and can express B7-H1 that stimulates T cells Blood 2005, 105, 2428-2435.
70. Yu, H.; Pardoll, D.; Jove, R. STATs in cancer inflammation and immunity: A leading role for STAT3. Nat. Rev. Cancer 2009, 9, 798-809.
71. Gibbs, C.P.; Kukekov, V.G.; Reith, J.D.; Tchigrinova, O.; Suslov, O.N.; Scott, E.W.; Ghivizzani, S.C.; Ignatova, T.N.; Steindler, D.A. Stem-like cells in bone sarcomas: Implications for tumorigenesis. Neoplasia 2005, 7, 967-976.
72. Cao, Y.; Lathia, J.D.; Eyler, C.E.; Wu, Q.; Li, Z.; Wang, H.; McLendon, R.E.; Hjelmeland, A.B.; Rich, J.N. Erythropoietin receptor signaling through stat3 is required for glioma stem cell maintenance. Genes Cancer 2010, 1, 50-61.
73. Villalva, C; Martin-Lanneree, 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, 826-838.
74. Wu, A.; Wei, J.; Kong, L.Y.; Wang, Y.; Priebe, W.; Qiao, W.; Sawaya, R.; Heimberger, A.B. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro. Oncol. 2010, 12, 1113-1125.
75. Wang, X.; Wang, G.; Zhao, Y.; Liu, X.; Ding, Q.; Shi, J.; Ding, Y.; Wang, S. STAT3 mediates resistance of CD44(+)CD24(-/low) breast cancer stem cells to tamoxifen in vitro. J. Biomed. Res. 2012, 26, 325-335.
76. Tseng, L.M.; Huang, P.I.; Chen, Y.R.; Chen, Y.C.; Chou, Y.C.; Chen, Y.W.; Chang, Y.L.; Hsu, H.S.; Lan, Y.T.; Chen, K.H. et al. Targeting signal transducer and activator of transcription 3 pathway by cucurbitacin I diminishes self-renewing and radiochemoresistant abilities in thyroid cancer-derived CD133+ cells. J. Pharmacol. Exp. Ther. 2012, 341, 410-423.
77. Hellsten, R; Johansson, M.; Dahlman, A.; Sterner, O.; Bjartell, A. Galiellalactone inhibits stem cell-like ALDH-positive prostate cancer cells. PLoS One 2011, 6, e22118.
78. Bromberg, J.F.; Wrzeszczynska, M.H.; Devgan, G; Zhao, Y.; Pestell, R.G; Albanese, C; Darnell, J.E., Jr. Stat3 as an oncogene. Cell 1999, 98, 295-303.
79. Liang, H.; Venema, V.J.; Wang, X.; Ju, H.; Venema, R.C.; Marrero, M.B. Regulation of angiotensin II-induced phosphorylation of STAT3 in vascular smooth muscle cells. J. Biol. Chem 1999, 274, 19846-19851.
80. Arvanitakis, L.; Geras-Raaka, E.; Varma, A.; Gershengorn, M.C.; Cesarman, E. Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 1997, 385, 347-350.
81. Cesarman, E.; Nador, R.G; Bai, F.; Bohenzky, R.A.; Russo, J.J.; Moore, P.S.; Chang, Y.; Knowles, D.M. Kaposi's sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi's sarcoma and malignant lymphoma. J. Virol. 1996, 70, 8218-8223.
82. Jiang, H.; Wu, D.; Simon, M.I. The transforming activity of activated G alpha 12. FEBS Lett. 1993, 330, 319-322.
83. Kalinec, G; Nazarali, A.J.; Hermouet, S.; Xu, N.; Gutkind, J.S. Mutated alpha subunit of the Gq protein induces malignant transformation in NIH 3T3 cells. Mol. Cell Biol. 1992, 12, 4687-4693.
84. Vara Prasad, M.V.; Shore, S.K.; Dhanasekaran, N. Activated mutant of G alpha 13 induces Egr-1, c-fos, and transformation in NIH 3T3 cells. Oncogene 1994, 9, 2425-2429.
85. Corre, I.; Baumann, H.; Hermouet, S. Regulation by Gi2 proteins of v-fms-induced proliferation and transformation via Src-kinase and STAT3. Oncogene 1999, 18, 6335-6342.
86. Ram, P.T.; Iyengar, R. G protein coupled receptor signaling through the Src and Stat3 pathway: Role in proliferation and transformation. Oncogene 2001, 20, 1601-1606.
87. Thomas, S.M.; Brugge, J.S. Cellular functions regulated by Src family kinases. Annu. Rev. Cell Dev. Biol. 1997, 13, 513-609.
88. Brown, M.T.; Cooper, J.A. Regulation, substrates and functions of src. Biochim. Biophys. Acta 1996, 1287, 121-149.
89. Bromberg, J.F.; Horvath, C.M.; Besser, D.; Lathem, W.W.; Darnell, J.E., Jr. Stat3 activation is required for cellular transformation by v-src. Mol. Cell Biol. 1998, 18, 2553-2558.
90. Turkson, J.; Bowman, T.; Adnane, J.; Zhang, Y.; Djeu, J.Y.; Sekharam, M.; Frank, D.A.; Holzman, L.B.; Wu, J.; Sebti, S. et al. Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein. Mol. Cell Biol. 1999, 19, 7519-7528.
91. Bowman, T.; Broome, M.A.; Sinibaldi, D.; Wharton, W.; Pledger, W.J.; Sedivy, J.M.; Irby, R.; Yeatman, T.; Courtneidge, S.A.; Jove, R. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc. Natl. Acad. Sci. USA 2001, 98, 7319-7324.
92. Ceresa, B.P.; Horvath, C.M.; Pessin, J.E. Signal transducer and activator of transcription-3 serine phosphorylation by insulin is mediated by a Ras/Raf/MEK-dependent pathway. Endocrinology 1997, 138, 413-4137.
93. Goi, T.; Shipitsin, M.; Lu, Z.; Foster, D.A.; Klinz, S.G.; Feig, L.A. An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity. EMBO J. 2000, 19, 623-630.
94. Ullrich, A.; Schlessinger, J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990, 61, 203-212.
95. Yarden, Y.; Ullrich, A. Growth factor receptor tyrosine kinases. Annu. Rev. Biochem. 1988, 57, 443-478.
96. Park, O.K.; Schaefer, T.S.; Nathans, D. In vitro activation of Stat3 by epidermal growth factor receptor kinase. Proc. Natl. Acad. Sci. USA 1996, 93, 13704-13708.
97. Kaptein, A.; Paillard, V.; Saunders, M. Dominant negative stat3 mutant inhibits interleukin-6-induced Jak-STAT signal transduction. J. Biol. Chem. 1996, 271, 5961-5964.
98. Stahl, N.; Farruggella, T.J.; Boulton, T.G.; Zhong, Z.; Darnell, J.E., Jr.; Yancopoulos, G.D. Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science 1995, 267, 1349-1353.
99. Shuai, K.; Ziemiecki, A.; Wilks, A.F.; Harpur, A.G.; Sadowski, H.B.; Gilman, M.Z.; Darnell, J.E. Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Nature 1993, 366, 580-583.
100. Wright, J.D.; Reuter, C.W.; Weber, M.J. An incomplete program of cellular tyrosine phosphorylations induced by kinase-defective epidermal growth factor receptors. J. Biol. Chem. 1995, 270, 12085-12093.
101. Ihle, J.N.; Kerr, I.M. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 1995, 11, 69-74.
102. Ihle, J.N.; Witthuhn, B.A.; Quelle, F.W.; Yamamoto, K.; Thierfelder, W.E.; Kreider, B.; Silvennoinen, O. Signaling by the cytokine receptor superfamily: JAKs and STATs. Trends Biochem. Sci. 1994, 19, 222-227.
103. Muller, M.; Briscoe, J.; Laxton, C.; Guschin, D.; Ziemiecki, A.; Silvennoinen, O.; Harpur, A.G.; Barbieri, G.; Witthuhn, B.A.; Schindler, C. et al. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature 1993, 366, 129-135.
104. Wilks, A.F. Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction. Proc. Natl. Acad. Sci. USA 1989, 86, 1603-1607.
105. Heim, M.H.; Kerr, I.M.; Stark, G.R.; Darnell, J.E., Jr. Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway. Science 1995, 267, 1347-1349.
106. Luo, F.; Xu, Y.; Ling, M.; Zhao, Y.; Xu, W.; Liang, X.; Jiang, R.; Wang, B.; Bian, Q.; Liu, Q. Arsenite evokes IL-6 secretion, autocrine regulation of STAT3 signaling, and miR-21 expression processes involved in the EMT and malignant transformation of human bronchial epithelial cells. Toxicol. Appl. Pharmacol. 2013, 273, 27-34.
107. Chan, K.S.; Sano, S.; Kiguchi, K.; Anders, J.; Komazawa, N.; Takeda, J.; DiGiovanni, J. Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J. Clin. Investig. 2004, 114, 720-728.
108. Chan, K.S.; Sano, S.; Kataoka, K.; Abel, E.; Carbajal, S.; Beltran, L.; Clifford, J.; Peavey, M.; Shen, J.; Digiovanni, J. Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis. Oncogene 2008, 27, 1087-1094.
109. Kataoka, K.; Kim, D.J.; Carbajal, S.; Clifford, J.L.; DiGiovanni, J. Stage-specific disruption of Stat3 demonstrates a direct requirement during both the initiation and promotion stages of mouse skin tumorigenesis. Carcinogenesis 2008, 29, 1108-1114.
110. De Andrea, M.; Ritta, M.; Landini, M.M.; Borgogna, C.; Mondini, M.; Kern, F.; Ehrenreiter, K.; Baccarini, M.; Marcuzzi, G.P.; Smola, S. et al. Keratinocyte-specific stat3 heterozygosity impairs development of skin tumors in human papillomavirus 8 transgenic mice. Cancer Res. 2010, 70, 7938-7948.
111. Blando, J.M.; Carbajal, S.; Abel, E.; Beltran, L.; Conti, C.; Fischer, S.; DiGiovanni, J. Cooperation between Stat3 and Akt signaling leads to prostate tumor development in transgenic mice. Neoplasia 2011, 13, 254-265.
112. Koskela, H.L.; Eldfors, S.; Ellonen, P.; van Adrichem, A.J.; Kuusanmaki, H.; Andersson, E.I.; Lagstrom, S.; Clemente, M.J.; Olson, T.; Jalkanen, S.E. et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N. Engl. J. Med. 2012, 366, 1905-1913.
113. Marotta, L.L.; Almendro, V.; Marusyk, A.; Shipitsin, M.; Schemme, J.; Walker, S.R.; Bloushtain-Qimron, N.; Kim, J.J.; Choudhury, S.A.; Maruyama, R. et al. The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(-) stem cell-like breast cancer cells in human tumors. J. Clin. Investig. 2011, 121, 2723-2735.
114. Al-Hajj, M.; Wicha, M.S.; Benito-Hernandez, A.; Morrison, S.J.; Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 2003, 100, 3983-3988.
115. Kim, S.Y.; Kang, J.W.; Song, X.; Kim, B.K.; Yoo, Y.D.; Kwon, Y.T.; Lee, Y.J. Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells. Cell. Signal. 2013, 25, 961-969.
116. Mangelsdorf, D.J.; Thummel, C.; Beato, M.; Herrlich, P.; Schutz, G.; Umesono, K.; Blumberg, B.; Kastner, P.; Mark, M.; Chambon, P. et al. The nuclear receptor superfamily: The second decade. Cell 1995, 83, 835-839.
117. Ferriere, F.; Habauzit, D.; Pakdel, F.; Saligaut, C.; Flouriot, G. Unliganded estrogen receptor alpha promotes PC12 survival during serum starvation. PLoS One 2013, 8, e69081.
118. De Miguel, F.; Lee, S.O.; Onate, S.A.; Gao, A.C. Stat3 enhances transactivation of steroid hormone receptors. Nucl. Recept. 2003, 1, 3.
119. Yeh, Y.T.; Ou-Yang, F.; Chen, I.F.; Yang, S.F.; Wang, Y.Y.; Chuang, H.Y.; Su, J.H.; Hou, M.F.; Yuan, S.S. STAT3 ser727 phosphorylation and its association with negative estrogen receptor status in breast infiltrating ductal carcinoma. Int. J. Cancer 2006, 118, 2943-2947.
120. Yamamoto, T.; Matsuda, T.; Junicho, A.; Kishi, H.; Saatcioglu, F.; Muraguchi, A. Cross-talk between signal transducer and activator of transcription 3 and estrogen receptor signaling. FEBS Lett. 2000, 486, 143-148.
121. Wang, L.H.; Yang, X.Y.; Mihalic, K.; Xiao, W.; Li, D.; Farrar, W.L. Activation of estrogen receptor blocks interleukin-6-inducible cell growth of human multiple myeloma involving molecular cross-talk between estrogen receptor and STAT3 mediated by co-regulator PIAS3. J. Biol. Chem. 2001, 276, 31839-31844.
122. Lee, H.; Zhang, P.; Herrmann, A.; Yang, C.; Xin, H.; Wang, Z.; Hoon, D.S.; Forman, S.J.; Jove, R.; Riggs, A.D. et al. Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation. Proc. Natl. Acad. Sci. USA 2012, 109, 7765-7769.
123. Suba, Z. Triple-negative breast cancer risk in women is defined by the defect of estrogen signaling: Preventive and therapeutic implications. Onco Targets Ther. 2014, 7, 147-164.
124. Schuringa, J.J.; Schepers, H.; Vellenga, E.; Kruijer, W. Ser727-dependent transcriptional activation by association of p300 with STAT3 upon IL-6 stimulation. FEBS Lett. 2001, 495, 71-76.
125. Lewis, J.S.; Jordan, V.C. Selective estrogen receptor modulators (SERMs): Mechanisms of anticarcinogenesis and drug resistance. Mutat. Res. 2005, 591, 247-263.
126. Neuman, E.; Ladha, M.H.; Lin, N.; Upton, T.M.; Miller, S.J.; DiRenzo, J.; Pestell, R.G.; Hinds, P.W.; Dowdy, S.F.; Brown, M. et al. Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. Mol. Cell Biol. 1997, 17, 5338-5347.
127. Zwijsen, R.M.; Wientjens, E.; Klompmaker, R.; van der Sman, J.; Bernards, R.; Michalides, R.J. CDK-independent activation of estrogen receptor by cyclin D1. Cell 1997, 88, 405-415.
128. Stendahl, M.; Kronblad, A.; Ryden, L.; Emdin, S.; Bengtsson, N.O.; Landberg, G. Cyclin D1 overexpression is a negative predictive factor for tamoxifen response in postmenopausal breast cancer patients. Br. J. Cancer 2004, 90, 1942-1948.
129. Jirstrom, K.; Stendahl, M.; Ryden, L.; Kronblad, A.; Bendahl, P.O.; Stal, O.; Landberg, G. Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Cancer Res. 2005, 65, 8009-8016.
130. Ishii, Y.; Waxman, S.; Germain, D. Tamoxifen stimulates the growth of cyclin D1-overexpressing breast cancer cells by promoting the activation of signal transducer and activator of transcription 3. Cancer Ress 2008, 68, 852-860.
131. Klampfer, L. The role of signal transducers and activators of transcription in colon cancer. Front. Biosci. 2008, 13, 2888-2899.
132. Alexandrow, M.G.; Song, L.J.; Altiok, S.; Gray, J.; Haura, E.B.; Kumar, N.B. Curcumin: A novel Stat3 pathway inhibitor for chemoprevention of lung cancer. Eur. J. Cancer Prev. 2012, 21, 407-412.
133. Kroon, P.; Berry, P.A.; Stower, M.J.; Rodrigues, G.; Mann, V.M.; Simms, M.; Bhasin, D.; Chettiar, S.; Li, C.; Li, P.K. et al. JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells. Cancer Res. 2013, 73, 5288-5298.
134. Hossain, D.M.; Dos Santos, C.; Zhang, Q.; Kozlowska, A.; Liu, H.; Gao, C.; Moreira, D.; Swiderski, P.; Jozwiak, A.; Kline, J. et al. Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity. Blood 2014, 123, 15-25.
135. 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, 315-324.
136. Debnath, B.; Xu, S.; Neamati, N. Small molecule inhibitors of signal transducer and activator of transcription 3 (Stat3) protein. J. Med. Chem. 2012, 55, 6645-6668.
137. Deng, J.; Grande, F.; Neamati, N. Small molecule inhibitors of Stat3 signaling pathway. Curr. Cancer Drug Targets 2007, 7, 91-107.
138. Dhanik, A.; McMurray, J.S.; Kavraki, L.E. Binding modes of peptidomimetics designed to inhibit STAT3. PLoS One 2012, 7, e51603.
139. Turkson, J.; Ryan, D.; Kim, J.S.; Zhang, Y.; Chen, Z.; Haura, E.; Laudano, A.; Sebti, S.; Hamilton, A.D.; Jove, R. Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. J. Biol. Chem. 2001, 276, 45443-45455.
140. Siddiquee, K.A.; Gunning, P.T.; Glenn, M.; Katt, W.P.; Zhang, S.; Schrock, C.; Sebti, S.M.; Jove, R.; Hamilton, A.D.; Turkson, J. An oxazole-based small-molecule Stat3 inhibitor modulates Stat3 stability and processing and induces antitumor cell effects. ACS Chem. Biol. 2007, 2, 787-798.
141. Zhang, X.; Sun, Y.; Pireddu, R.; Yang, H.; Urlam, M.K.; Lawrence, H.R.; Guida, W.C.; Lawrence, N.J.; Sebti, S.M. A novel inhibitor of STAT3 homodimerization selectively suppresses STAT3 activity and malignant transformation. Cancer Res. 2013, 73, 1922-1933.
142. Kumar, A.; Bora, U. Molecular docking studies on inhibition of Stat3 dimerization by curcumin natural derivatives and its conjugates with amino acids. Bioinformation 2012, 8, 988-993.
143. 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, 193-202.
144. 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, 4700-4705.
145. 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, 1235-1242.
146. Fletcher, S.; Page, B.D.; Zhang, X.; Yue, P.; Li, Z.H.; Sharmeen, S.; Singh, J.; Zhao, W.; Schimmer, A.D.; Trudel, S. et al. Antagonism of the Stat3-Stat3 protein dimer with salicylic acid based small molecules. Chem. Med. Chem. 2011, 6, 1459-1470.
147. Zhang, X.; Yue, P.; Page, B.D.; Li, T.; Zhao, W.; Namanja, A.T.; Paladino, D.; Zhao, J.; Chen, Y.; Gunning, P.T. et al. Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proc. Natl. Acad. Sci. USA 2012, 109, 9623-9628.
148. Reed, S.; Li, H.; Li, C.; Lin, J. Celecoxib inhibits STAT3 phosphorylation and suppresses cell migration and colony forming ability in rhabdomyosarcoma cells. Biochem. Biophys. Res. Commun. 2011, 407, 450-455.
149. Zhao, W.; Jaganathan, S.; Turkson, J. A cell-permeable Stat3 SH2 domain mimetic inhibits Stat3 activation and induces antitumor cell effects in vitro. J. Biol. Chem. 2010, 285, 35855-35865.
150. Lin, Y.M.; Wang, C.M.; Jeng, J.C.; Leprince, D.; Shih, H.M. HIC1 interacts with and modulates the activity of STAT3. Cell Cycle 2013, 12, 2266-2276.
151. Turkson, J.; Zhang, S.; Palmer, J.; Kay, H.; Stanko, J.; Mora, L.B.; Sebti, S.; Yu, H.; Jove, R. Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity. Mol. Cancer Ther. 2004, 3, 1533-1542.
152. Nagel-Wolfrum, K.; Buerger, C.; Wittig, I.; Butz, K.; Hoppe-Seyler, F.; Groner, B. The interaction of specific peptide aptamers with the DNA binding domain and the dimerization domain of the transcription factor Stat3 inhibits transactivation and induces apoptosis in tumor cells. Mol. Cancer Res. 2004, 2, 170-182.
153. Timofeeva, O.A.; Tarasova, N.I.; Zhang, X.; Chasovskikh, S.; Cheema, A.K.; Wang, H.; Brown, M.L.; Dritschilo, A. STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain. Proc. Natl. Acad. Sci. USA 2013, 110, 1267-1272.
154. Jing, N.; Li, Y.; Xu, X.; Sha, W.; Li, P.; Feng, L.; Tweardy, D.J. Targeting Stat3 with G-quartet oligodeoxynucleotides in human cancer cells. DNA Cell Biol. 2003, 22, 685-696.
155. Zhu, Q.; Jing, N. Computational study on mechanism of G-quartet oligonucleotide T40214 selectively targeting Stat3. J. Comput. Aided Mol. Des. 2007, 21, 641-648.
156. Jing, N.; Zhu, Q.; Yuan, P.; Li, Y.; Mao, L.; Tweardy, D.J. Targeting signal transducer and activator of transcription 3 with G-quartet oligonucleotides: A potential novel therapy for head and neck cancer. Mol. Cancer Ther. 2006, 5, 279-286.
157. Jing, N.; Li, Y.; Xiong, W.; Sha, W.; Jing, L.; Tweardy, D.J. G-quartet oligonucleotides: A new class of signal transducer and activator of transcription 3 inhibitors that suppresses growth of prostate and breast tumors through induction of apoptosis. Cancer Res. 2004, 64, 6603-6609.
158. Gao, L.F.; Xu, D.Q.; Wen, L.J.; Zhang, X.Y.; Shao, Y.T.; Zhao, X.J. Inhibition of STAT3 expression by siRNA suppresses growth and induces apoptosis in laryngeal cancer cells. Acta Pharmacol. Sin. 2005, 26, 377-383.
159. Kunigal, S.; Lakka, S.S.; Sodadasu, P.K.; Estes, N.; Rao, J.S. Stat3-siRNA induces Fas-mediated apoptosis in vitro and in vivo in breast cancer. Int. J. Oncol. 2009, 34, 1209-1220.
160. Verma, N.K.; Davies, A.M.; Long, A.; Kelleher, D.; Volkov, Y. STAT3 knockdown by siRNA induces apoptosis in human cutaneous T-cell lymphoma line Hut78 via downregulation of Bcl-xL. Cell Mol. Biol. Lett. 2010, 15, 342-355.
161. Liang, Z.W.; Guo, B.F.; Li, Y.; Li, X.J.; Li, X.; Zhao, L.J.; Gao, L.F.; Yu, H.; Zhao, X.J.; Zhang, L. et al. Plasmid-based Stat3 siRNA delivered by hydroxyapatite nanoparticles suppresses mouse prostate tumour growth in vivo. Asian J. Androl. 2011, 13, 481-486.
162. Hong, J.; Zhao, Y.; Huang, W. Blocking c-myc and stat3 by E. coli expressed and enzyme digested siRNA in mouse melanoma. Biochem. Biophys. Res. Commun. 2006, 348, 600-605.
163. Buerger, C.; Nagel-Wolfrum, K.; Kunz, C.; Wittig, I.; Butz, K.; Hoppe-Seyler, F.; Groner, B. Sequence-specific peptide aptamers, interacting with the intracellular domain of the epidermal growth factor receptor, interfere with Stat3 activation and inhibit the growth of tumor cells. J. Biol. Chem. 2003, 278, 37610-37621.
164. Ge, H.; Liu, H.; Fu, Z.; Sun, Z. Therapeutic and preventive effects of an epidermal growth factor receptor inhibitor on oral squamous cell carcinoma. J. Int. Med. Res. 2012, 40, 455-466.
165. Li, S.Q.; Cheuk, A.T.; Shern, J.F.; Song, Y.K.; Hurd, L.; Liao, H.; Wei, J.S.; Khan, J. Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534). PLoS One 2013, 8, e76551.
166. Huang, C.; Cao, J.; Huang, K.J.; Zhang, F.; Jiang, T.; Zhu, L.; Qiu, Z.J. Inhibition of STAT3 activity with AG490 decreases the invasion of human pancreatic cancer cells in vitro. Cancer Sci. 2006, 97, 1417-1423.
167. Gupta, S.C.; Phromnoi, K.; Aggarwal, B.B. Morin inhibits STAT3 tyrosine 705 phosphorylation in tumor cells through activation of protein tyrosine phosphatase SHP1. Biochem. Pharmacol. 2013, 85, 898-912.
168. Ferrajoli, A.; Faderl, S.; Van, Q.; Koch, P.; Harris, D.; Liu, Z.; Hazan-Halevy, I.; Wang, Y.; Kantarjian, H.M.; Priebe, W. et al. WP1066 disrupts Janus kinase-2 and induces caspase-dependent apoptosis in acute myelogenous leukemia cells. Cancer Res. 2007, 67, 11291-11299.
169. Iwamaru, A.; Szymanski, S.; Iwado, E.; Aoki, H.; Yokoyama, T.; Fokt, I.; Hess, K.; Conrad, C.; Madden, T.; Sawaya, R. et al. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene 2007, 26, 2435-2444.
170. Pardanani, A.; Hood, J.; Lasho, T.; Levine, R.L.; Martin, M.B.; Noronha, G.; Finke, C.; Mak, C.C.; Mesa, R.; Zhu, H. et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia 2007, 21, 1658-1668.
171. Scuto, A.; Krejci, P.; Popplewell, L.; Wu, J.; Wang, Y.; Kujawski, M.; Kowolik, C.; Xin, H.; Chen, L.; Kretzner, L. et al. The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia 2011, 25, 538-550.
172. Yan, S.; Li, Z.; Thiele, C.J. Inhibition of STAT3 with orally active JAK inhibitor, AZD1480, decreases tumor growth in Neuroblastoma and Pediatric Sarcomas in vitro and in vivo. Oncotarget 2013, 4, 433-445.
173. Chen, Z.; Lee, F.Y.; Bhalla, K.N.; Wu, J. Potent inhibition of platelet-derived growth factor-induced responses in vascular smooth muscle cells by BMS-354825 (dasatinib). Mol. Pharmacol. 2006, 69, 1527-1533.
174. Michels, S.; Trautmann, M.; Sievers, E.; Kindler, D.; Huss, S.; Renner, M.; Friedrichs, N.; Kirfel, J.; Steiner, S.; Endl, E. et al. SRC signaling is crucial in the growth of synovial sarcoma cells. Cancer Res. 2013, 73, 2518-2528.
175. Chang, A.Y.; Wang, M. Molecular mechanisms of action and potential biomarkers of growth inhibition of dasatinib (BMS-354825) on hepatocellular carcinoma cells. BMC Cancer 2013, 13, 267.
176. Premkumar, D.R.; Jane, E.P.; Agostino, N.R.; Scialabba, J.L.; Pollack, I.F. Dasatinib synergizes with JSI-124 to inhibit growth and migration and induce apoptosis of malignant human glioma cells. J. Carcinog. 2010, doi:10.4103/1477-3163.65448.
177. Rice, L.; Lepler, S.; Pampo, C.; Siemann, D.W. Impact of the SRC inhibitor dasatinib on the metastatic phenotype of human prostate cancer cells. Clin. Exp. Metastasis 2012, 29, 133-142.
178. Oyaizu, T.; Fung, S.Y.; Shiozaki, A.; Guan, Z.; Zhang, Q.; dos Santos, C.C.; Han, B.; Mura, M.; Keshavjee, S.; Liu, M. Src tyrosine kinase inhibition prevents pulmonary ischemia-reperfusion-induced acute lung injury. Intensive Care Med. 2012, 38, 894-905.
179. Antonarakis, E.S.; Heath, E.I.; Posadas, E.M.; Yu, E.Y.; Harrison, M.R.; Bruce, J.Y.; Cho, S.Y.; Wilding, G.E.; Fetterly, G.J.; Hangauer, D.G. et al. A phase 2 study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer. Cancer Chemother. Pharmacol. 2013, 71, 883-892.
180. Gangadhar, T.C.; Clark, J.I.; Karrison, T.; Gajewski, T.F. Phase II study of the Src kinase inhibitor saracatinib (AZD0530) in metastatic melanoma. Investig. New Drugs 2013, 31, 769-773.
181. Nam, S.; Wen, W.; Schroeder, A.; Herrmann, A.; Yu, H.; Cheng, X.; Merz, K.H.; Eisenbrand, G.; Li, H.; Yuan, Y.C. et al. Dual inhibition of Janus and Src family kinases by novel indirubin derivative blocks constitutively-activated Stat3 signaling associated with apoptosis of human pancreatic cancer cells. Mol. Oncol. 2013, 7, 369-378.
182. Liu, L.; Gaboriaud, N.; Vougogianopoulou, K.; Tian, Y.; Wu, J.; Wen, W.; Skaltsounis, A.L.; Jove, R. MLS-2384, a new 6-bromoindirubin derivative with dual JAK/Src kinase inhibitory activity, suppresses growth of diverse cancer cells. Cancer Biol. Ther. 2013, 15.
183. Kim, B.H.; Won, C.; Lee, Y.H.; Choi, J.S.; Noh, K.H.; Han, S.; Lee, H.; Lee, C.S.; Lee, D.S.; Ye, S.K. et al. Sophoraflavanone G induces apoptosis of human cancer cells by targeting upstream signals of STATs. Biochem. Pharmacol. 2013, 86, 950-959.
184. Jung, J.H.; Kwon, T.R.; Jeong, S.J.; Kim, E.O.; Sohn, E.J.; Yun, M.; Kim, S.H. Apoptosis induced by tanshinone IIA and cryptotanshinone is mediated by distinct JAK/STAT3/5 and SHP1/2 signaling in chronic myeloid leukemia K562 cells. Evid. Based Complement. Alternat. Med. 2013, 2013, 805639.
185. Kang, Y.; Park, M.A.; Heo, S.W.; Park, S.Y.; Kang, K.W.; Park, P.H.; Kim, J.A. The radio-sensitizing effect of xanthohumol is mediated by STAT3 and EGFR suppression in doxorubicin-resistant MCF-7 human breast cancer cells. Biochim. Biophys. Acta 2013, 1830, 2638-2648.
186. Chen, X.; Du, Y.; Nan, J.; Zhang, X.; Qin, X.; Wang, Y.; Hou, J.; Wang, Q.; Yang, J. Brevilin A, A novel natural product, inhibits janus kinase activity and blocks STAT3 signaling in cancer cells. PLoS One 2013, 8, e63697.
187. Hutzen, B.; Willis, W.; Jones, S.; Cen, L.; Deangelis, S.; Fuh, B.; Lin, J. Dietary agent, benzyl isothiocyanate inhibits signal transducer and activator of transcription 3 phosphorylation and collaborates with sulforaphane in the growth suppression of PANC-1 cancer cells. Cancer Cell Int. 2009, 9, 24.
188. 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. et al. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc. Natl. Acad. Sci. USA 2007, 104, 7391-7396.
189. Page, B.D.; Fletcher, S.; Yue, P.; Li, Z.; Zhang, X.; Sharmeen, S.; Datti, A.; Wrana, J.L.; Trudel, S.; Schimmer, A.D. et al. Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain. Bioorg. Med. Chem. Lett. 2011, 21, 5605-5609.
190. Becker, S.; Groner, B.; Muller, C.W. Three-dimensional structure of the Stat3beta homodimer bound to DNA. Nature 1998, 394, 145-151.
191. 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, 799-809.
192. Souissi, I.; Najjar, I.; Ah-Koon, L.; Schischmanoff, P.O.; Lesage, D.; Le Coquil, S.; Roger, C.; Dusanter-Fourt, I.; Varin-Blank, N.; Cao, A. et al. A STAT3-decoy oligonucleotide induces cell death in a human colorectal carcinoma cell line by blocking nuclear transfer of STAT3 and STAT3-bound NF-kappaB. BMC Cell Biol. 2011, 12, 14.
193. Weerasinghe, P.; Garcia, G.E.; Zhu, Q.; Yuan, P.; Feng, L.; Mao, L.; Jing, N. Inhibition of Stat3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. Int. J. Oncol. 2007, 31, 129-136.
194. Leong, P.L.; Andrews, G.A.; Johnson, D.E.; Dyer, K.F.; Xi, S.; Mai, J.C.; Robbins, P.D.; Gadiparthi, S.; Burke, N.A.; Watkins, S.F. et al. Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc. Natl. Acad. Sci. USA 2003, 100, 4138-4143.
195. Sun, X.; Zhang, J.; Wang, L.; Tian, Z. Growth inhibition of human hepatocellular carcinoma cells by blocking STAT3 activation with decoy-ODN. Cancer Lett. 2008, 262, 201-213.
196. Zhang, X.; Zhang, J.; Wang, L.; Wei, H.; Tian, Z. Therapeutic effects of STAT3 decoy oligodeoxynucleotide on human lung cancer in xenograft mice. BMC Cancer 2007, 7, 149.
197. Xi, S.; Gooding, W.E.; Grandis, J.R. In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: Implications for cancer therapy. Oncogene 2005, 24, 970-979.
198. Nielsen, M.; Kaltoft, K.; Nordahl, M.; Ropke, C.; Geisler, C.; Mustelin, T.; Dobson, P.; Svejgaard, A.; Odum, N. Constitutive activation of a slowly migrating isoform of Stat3 in mycosis fungoides: Tyrphostin AG490 inhibits Stat3 activation and growth of mycosis fungoides tumor cell lines. Proc. Natl. Acad. Sci. USA 1997, 94, 6764-6769.
199. Seltana, A.; Guezguez, A.; Lepage, M.; Basora, N.; Beaulieu, J.F. Src family kinase inhibitor PP2 accelerates differentiation in human intestinal epithelial cells. Biochem. Biophys. Res. Commun. 2013, 430, 1195-1200.
200. Aggarwal, B.B.; Kumar, A.; Bharti, A.C. Anticancer potential of curcumin: Preclinical and clinical studies. Anticancer Res. 2003, 23, 363-398.
201. Ren, X.M.; Duan, L.; He, Q.A.; Zhang, Z.; Zhou, Y.; Wu, D.H.; Pan, J.X.; Pei, D.Q.; Ding, K. Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway. ACS Med. Chem. Lett. 2010, 1, 454-459.
202. Lippman, S.M. Cancer prevention research: Back to the future. Cancer Prev. Res. 2009, 2, 503-513.
203. Uray, I.P.; Brown, P.H. Chemoprevention of hormone receptor-negative breast cancer: New approaches needed. Recent Results Cancer Res. 2011, 188, 147-162.
204. Den Hollander, P.; Savage, M.I.; Brown, P.H. Targeted therapy for breast cancer prevention. Front. Oncol. 2013, 3, 250.