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BioMed Research International
Volume 2013 (2013), Article ID 421821, 15 pages
http://dx.doi.org/10.1155/2013/421821
Review Article

Role of STAT3 in Cancer Metastasis and Translational Advances

Gude lab, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India

Received 29 April 2013; Revised 25 August 2013; Accepted 26 August 2013

Academic Editor: Jeroen T. Buijs

Copyright © 2013 Mohammad Zahid Kamran et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. S. Akira, Y. Nishio, M. Inoue et al., “Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway,” Cell, vol. 77, no. 1, pp. 63–71, 1994. View at Scopus
  2. J. E. Darnell Jr., I. M. Kerr, and G. R. Stark, “Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins,” Science, vol. 264, no. 5164, pp. 1415–1421, 1994. View at Scopus
  3. J. E. Darnell Jr., “STATs and gene regulation,” Science, vol. 277, no. 5332, pp. 1630–1635, 1997. View at Publisher · View at Google Scholar · View at Scopus
  4. D. E. Levy, “Physiological significance of STAT proteins: investigations through gene disruption in vivo,” Cellular and Molecular Life Sciences, vol. 55, no. 12, pp. 1559–1567, 1999. View at Publisher · View at Google Scholar · View at Scopus
  5. N. G. Copeland, D. J. Gilbert, C. Schindler et al., “Distribution of the mammalian stat gene family in mouse chromosomes,” Genomics, vol. 29, no. 1, pp. 225–228, 1995. View at Publisher · View at Google Scholar · View at Scopus
  6. J. N. Ihle, “The Stat family in cytokine signaling,” Current Opinion in Cell Biology, vol. 13, no. 2, pp. 211–217, 2001. View at Publisher · View at Google Scholar · View at Scopus
  7. Z. Wen and J. E. Darnell 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 Research, vol. 25, no. 11, pp. 2062–2067, 1997. View at Publisher · View at Google Scholar · View at Scopus
  8. K. Yokogami, S. Wakisaka, J. Avruch, and S. A. Reeves, “Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR,” Current Biology, vol. 10, no. 1, pp. 47–50, 2000. View at Publisher · View at Google Scholar · View at Scopus
  9. T. Bowman, R. Garcia, J. Turkson, and R. Jove, “STATs in oncogenesis,” Oncogene, vol. 19, no. 21, pp. 2474–2488, 2000. View at Scopus
  10. R. Buettner, L. B. Mora, and R. Jove, “Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention,” Clinical Cancer Research, vol. 8, no. 4, pp. 945–954, 2002. View at Scopus
  11. S. Huang, “Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications,” Clinical Cancer Research, vol. 13, no. 5, pp. 1362–1366, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. G. Niu, R. Heller, R. Catlett-Falcone et al., “Gene therapy with dominant-negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo,” Cancer Research, vol. 59, no. 20, pp. 5059–5063, 1999. View at Scopus
  13. R. Garcia, C.-L. Yu, A. Hudnall et al., “Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells,” Cell Growth and Differentiation, vol. 8, no. 12, pp. 1267–1276, 1997. View at Scopus
  14. D. W. Leaman, S. Leung, X. Li, and G. R. Stark, “Regulation of STAT-dependent pathways by growth factors and cytokines,” FASEB Journal, vol. 10, no. 14, pp. 1578–1588, 1996. View at Scopus
  15. C.-L. Yu, D. J. Meyer, G. S. Campbell et al., “Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein,” Science, vol. 269, no. 5220, pp. 81–83, 1995. View at Scopus
  16. R. L. Ilaria Jr. and R. A. Van Etten, “P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members,” Journal of Biological Chemistry, vol. 271, no. 49, pp. 31704–31710, 1996. View at Publisher · View at Google Scholar · View at Scopus
  17. J. Turkson, T. Bowman, J. Adnane et al., “Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein,” Molecular and Cellular Biology, vol. 19, no. 11, pp. 7519–7528, 1999. View at Scopus
  18. J. Chung, E. Uchida, T. C. Grammer, and J. Blenis, “STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation,” Molecular and Cellular Biology, vol. 17, no. 11, pp. 6508–6516, 1997. View at Scopus
  19. N. Jain, T. Zhang, W. H. Kee, W. Li, and X. Cao, “Protein kinase C δ associates with and phosphorylates Stat3 in an interleukin-6-dependent manner,” Journal of Biological Chemistry, vol. 274, no. 34, pp. 24392–24400, 1999. View at Publisher · View at Google Scholar · View at Scopus
  20. H. Kojima, T. Sasaki, T. Ishitani et al., “STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFβ-activated kinase 1 for STAT3 Ser-727 phosphorylation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 12, pp. 4524–4529, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. Z.-L. Yuan, Y.-J. Guan, D. Chatterjee, and Y. E. Chin, “Stat3 dimerization regulated by reversible acetylation of a single lysine residue,” Science, vol. 307, no. 5707, pp. 269–273, 2005. View at Publisher · View at Google Scholar · View at Scopus
  22. W. Chen, M. O. Daines, and G. K. Khurana Hershey, “Turning off signal transducer and activator of transcription (STAT): the negative regulation of STAT signaling,” Journal of Allergy and Clinical Immunology, vol. 114, no. 3, pp. 476–489, 2004. View at Publisher · View at Google Scholar · View at Scopus
  23. B. G. Neel and N. K. Tonks, “Protein tyrosine phosphatases in signal transduction,” Current Opinion in Cell Biology, vol. 9, no. 2, pp. 193–204, 1997. View at Publisher · View at Google Scholar · View at Scopus
  24. J. N. Andersen, O. H. Mortensen, G. H. Peters et al., “Structural and evolutionary relationships among protein tyrosine phosphatase domains,” Molecular and Cellular Biology, vol. 21, no. 21, pp. 7117–7136, 2001. View at Publisher · View at Google Scholar · View at Scopus
  25. J. Irie-Sasaki, T. Sasaki, W. Matsumoto et al., “CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling,” Nature, vol. 409, no. 6818, pp. 349–354, 2001. View at Publisher · View at Google Scholar · View at Scopus
  26. Y. Han, H. M. Amin, B. Franko, C. Frantz, X. Shi, and R. Lai, “Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma,” Blood, vol. 108, no. 8, pp. 2796–2803, 2006. View at Publisher · View at Google Scholar · View at Scopus
  27. E. A. Bard-Chapeau, S. Li, J. Ding et al., “Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis,” Cancer Cell, vol. 19, no. 5, pp. 629–639, 2011. View at Publisher · View at Google Scholar · View at Scopus
  28. H. Liang, V. J. Venema, X. Wang, H. Ju, R. C. Venema, and M. B. Marrero, “Regulation of angiotensin II-induced phosphorylation of STAT3 in vascular smooth muscle cells,” Journal of Biological Chemistry, vol. 274, no. 28, pp. 19846–19851, 1999. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Rigacci, D. Talini, and A. Berti, “LMW-PTP associates and dephosphorylates STAT5 interacting with its C-terminal domain,” Biochemical and Biophysical Research Communications, vol. 312, no. 2, pp. 360–366, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. K. Shuai and B. Liu, “Regulation of gene-activation pathways by pias proteins in the immune system,” Nature Reviews Immunology, vol. 5, no. 8, pp. 593–605, 2005. View at Publisher · View at Google Scholar · View at Scopus
  31. K. Shuai, “Modulation of STAT signaling by STAT-interacting proteins,” Oncogene, vol. 19, no. 21, pp. 2638–2644, 2000. View at Scopus
  32. B. Liu, J. Liao, X. Rao et al., “Inhibition of Stat1-mediated gene activation by PIAS1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 18, pp. 10626–10631, 1998. View at Publisher · View at Google Scholar · View at Scopus
  33. C. D. Chung, J. Liao, B. Liu et al., “Specific inhibition of Stat3 signal transduction by PIAS3,” Science, vol. 278, no. 5344, pp. 1803–1805, 1997. View at Publisher · View at Google Scholar · View at Scopus
  34. B. Liu, M. Gross, J. Ten Hoeve, and K. Shuai, “A transcriptional corepressor of Stat1 with an essential LXXLL signature motif,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 6, pp. 3203–3207, 2001. View at Publisher · View at Google Scholar · View at Scopus
  35. T. Arora, B. Liu, H. He et al., “PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4,” Journal of Biological Chemistry, vol. 278, no. 24, pp. 21327–21330, 2003. View at Publisher · View at Google Scholar · View at Scopus
  36. T. Naka, M. Narazaki, M. Hirata et al., “Structure and function of a new STAT-induced STAT inhibitor,” Nature, vol. 387, no. 6636, pp. 924–929, 1997. View at Publisher · View at Google Scholar · View at Scopus
  37. T. A. Endo, M. Masuhara, M. Yokouchi et al., “A new protein containing an SH2 domain that inhibits JAK kinases,” Nature, vol. 387, no. 6636, pp. 921–924, 1997. View at Publisher · View at Google Scholar · View at Scopus
  38. R. Starr, T. A. Willson, E. M. Viney et al., “A family of cytokine-inducible inhibitors of signalling,” Nature, vol. 387, no. 6636, pp. 917–921, 1997. View at Publisher · View at Google Scholar · View at Scopus
  39. B. A. Croker, H. Kiu, and S. E. Nicholson, “SOCS regulation of the JAK/STAT signalling pathway,” Seminars in Cell and Developmental Biology, vol. 19, no. 4, pp. 414–422, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. J.-G. Zhang, A. Farley, S. E. Nicholson et al., “The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 5, pp. 2071–2076, 1999. View at Publisher · View at Google Scholar · View at Scopus
  41. J. F. Bromberg, M. H. Wrzeszczynska, G. Devgan et al., “Stat3 as an oncogene,” Cell, vol. 98, no. 3, pp. 295–303, 1999.
  42. J. Turkson, T. Bowman, R. Garcia, E. Caldenhoven, R. P. De Groot, and R. Jove, “Stat3 activation by Src induces specific gene regulation and is required for cell transformation,” Molecular and Cellular Biology, vol. 18, no. 5, pp. 2545–2552, 1998. View at Scopus
  43. C.-Y. Yu, L. Wang, A. Khaletskiy et al., “STAT3 activation is required for interleukin-6 induced transformation in tumor-promotion sensitive mouse skin epithelial cells,” Oncogene, vol. 21, no. 25, pp. 3949–3960, 2002. View at Publisher · View at Google Scholar · View at Scopus
  44. C. Miranda, T. Fumagalli, M. C. Anania et al., “Role of STAT3 in in vitro transformation triggered by TRK oncogenes,” PLoS One, vol. 5, no. 3, Article ID e9446, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. J. H. Hwang, D. W. Kim, J. M. Suh et al., “Activation of signal transducer and activator of transcription 3 by oncogenic RET/PTC (rearranged in transformation/papillary thyroid carcinoma) tyrosine kinase: roles in specific gene regulation and cellular transformation,” Molecular Endocrinology, vol. 17, no. 6, pp. 1155–1166, 2003. View at Publisher · View at Google Scholar · View at Scopus
  46. T. Yoshida, T. Hanada, T. Tokuhisa et al., “Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation,” Journal of Experimental Medicine, vol. 196, no. 5, pp. 641–653, 2002. View at Publisher · View at Google Scholar · View at Scopus
  47. A. Vultur, R. Arulanandam, J. Turkson, G. Niu, R. Jove, and L. Raptis, “Stat3 is required for full neoplastic transformation by the simian virus 40 large tumor antigen,” Molecular Biology of the Cell, vol. 16, no. 8, pp. 3832–3846, 2005. View at Publisher · View at Google Scholar · View at Scopus
  48. Y.-H. Chung, N.-H. Cho, M. I. Garcia, S.-H. Lee, P. Feng, and J. U. Jung, “Activation of Stat3 transcription factor by Herpesvirus Saimiri STP-A oncoprotein,” Journal of Virology, vol. 78, no. 12, pp. 6489–6497, 2004. View at Publisher · View at Google Scholar · View at Scopus
  49. D. A. Frank, “STAT3 as a central mediator of neoplastic cellular transformation,” Cancer Letters, vol. 251, no. 2, pp. 199–210, 2007. View at Publisher · View at Google Scholar · View at Scopus
  50. C. V. Dang, “c-Myc target genes involved in cell growth, apoptosis, and metabolism,” Molecular and Cellular Biology, vol. 19, no. 1, pp. 1–11, 1999. View at Scopus
  51. T. Shirogane, T. Fukada, J. M. M. Muller, D. T. Shima, M. Hibi, and T. Hirano, “Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis,” Immunity, vol. 11, no. 6, pp. 709–719, 1999. View at Scopus
  52. S. Bhattacharya, R. M. Ray, and L. R. Johnson, “STAT3-mediated transcription of Bcl-2, Mcl-1 and C-IAP2 prevents apoptosis in polyamine-depleted cells,” Biochemical Journal, vol. 392, part 2, pp. 335–344, 2005. View at Publisher · View at Google Scholar · View at Scopus
  53. G. Niu, K. L. Wright, Y. Ma et al., “Role of Stat3 in regulating p53 expression and function,” Molecular and Cellular Biology, vol. 25, no. 17, pp. 7432–7440, 2005. View at Publisher · View at Google Scholar · View at Scopus
  54. R. S. Chapman, P. C. Lourenco, E. Tonner et al., “Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3,” Genes and Development, vol. 13, no. 19, pp. 2604–2616, 1999. View at Publisher · View at Google Scholar · View at Scopus
  55. N. De La Iglesia, G. Konopka, S. V. Puram et al., “Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway,” Genes and Development, vol. 22, no. 4, pp. 449–462, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. C. Suiqing, Z. Min, and C. Lirong, “Overexpression of phosphorylated-STAT3 correlated with the invasion and metastasis of cutaneous squamous cell carcinoma,” Journal of Dermatology, vol. 32, no. 5, pp. 354–360, 2005. View at Scopus
  57. Z. Qiu, C. Huang, J. Sun et al., “RNA interference-mediated signal transducers and activators of transcription 3 gene silencing inhibits invasion and metastasis of human pancreatic cancer cells,” Cancer Science, vol. 98, no. 7, pp. 1099–1106, 2007. View at Publisher · View at Google Scholar · View at Scopus
  58. H. D. Li, C. Huang, K. J. Huang et al., “STAT3 knockdown reduces pancreatic cancer cell invasiveness and matrix metalloproteinase-7 expression in nude mice,” PLoS One, vol. 6, no. 10, Article ID e25941, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. T.-X. Xie, D. Wei, M. Liu et al., “Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis,” Oncogene, vol. 23, no. 20, pp. 3550–3560, 2004. View at Publisher · View at Google Scholar · View at Scopus
  60. T. N. Dechow, L. Pedranzini, A. Leitch et al., “Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 29, pp. 10602–10607, 2004. View at Publisher · View at Google Scholar · View at Scopus
  61. M. Itoh, T. Murata, T. Suzuki et al., “Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells,” Oncogene, vol. 25, no. 8, pp. 1195–1204, 2006. View at Publisher · View at Google Scholar · View at Scopus
  62. S. Sano, S. Itami, K. Takeda et al., “Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis,” The EMBO Journal, vol. 18, no. 17, pp. 4657–4668, 1999. View at Publisher · View at Google Scholar · View at Scopus
  63. D. L. Silver, H. Naora, J. Liu, W. Cheng, and D. J. Montell, “Activated signal transducer and activator of transcription (STAT) 3: localization in focal adhesions and function in ovarian cancer cell motility,” Cancer Research, vol. 64, no. 10, pp. 3550–3558, 2004. View at Publisher · View at Google Scholar · View at Scopus
  64. D. C. H. Ng, H. L. Bao, P. L. Cheh et al., “Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin,” Journal of Cell Biology, vol. 172, no. 2, pp. 245–257, 2006. View at Publisher · View at Google Scholar · View at Scopus
  65. T. S. Teng, B. Lin, E. Manser, D. C. H. Ng, and X. Cao, “Stat3 promotes directional cell migration by regulating Rac1 activity via its activator βPIX,” Journal of Cell Science, vol. 122, no. 22, pp. 4150–4159, 2009. View at Publisher · View at Google Scholar · View at Scopus
  66. M. Debidda, L. Wang, H. Zang, V. Poli, and Y. Zheng, “A role of STAT3 in Rho GTPase-regulated cell migration and proliferation,” Journal of Biological Chemistry, vol. 280, no. 17, pp. 17275–17285, 2005. View at Publisher · View at Google Scholar · View at Scopus
  67. J. Azare, K. Leslie, H. Al-Ahmadie et al., “Constitutively activated stat3 induces tumorigenesis and enhances cell motility of prostate epithelial cells through integrin β6,” Molecular and Cellular Biology, vol. 27, no. 12, pp. 4444–4453, 2007. View at Publisher · View at Google Scholar · View at Scopus
  68. P. Gassmann and J. Haier, “The tumor cell-host organ interface in the early onset of metastatic organ colonisation,” Clinical and Experimental Metastasis, vol. 25, no. 2, pp. 171–181, 2008. View at Publisher · View at Google Scholar · View at Scopus
  69. D. X. Nguyen, P. D. Bos, and J. Massagué, “Metastasis: from dissemination to organ-specific colonization,” Nature Reviews Cancer, vol. 9, no. 4, pp. 274–284, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. T. Wang, G. Niu, M. Kortylewski et al., “Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells,” Nature Medicine, vol. 10, no. 1, pp. 48–54, 2004. View at Publisher · View at Google Scholar · View at Scopus
  71. O. J. T. McCarty, S. A. Mousa, P. F. Bray, and K. Konstantopoulos, “Immobilized platelets support human colon carcinoma cell tethering, rolling, and firm adhesion under dynamic flow conditions,” Blood, vol. 96, no. 5, pp. 1789–1797, 2000. View at Scopus
  72. J. Grunstein, W. G. Roberts, O. Mathieu-Costello, D. Hanahan, and R. S. Johnson, “Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function,” Cancer Research, vol. 59, no. 7, pp. 1592–1598, 1999. View at Scopus
  73. K. H. Plate, G. Breier, H. A. Weich, and W. Risau, “Vascular endothelial growth factor is a potential tumour angiogenssis factor in human gliomas in vivo,” Nature, vol. 359, no. 6398, pp. 845–848, 1992. View at Publisher · View at Google Scholar · View at Scopus
  74. Z. Chen and C. H. Zhong, “STAT3: a critical transcription activator in angiogenesis,” Medicinal Research Reviews, vol. 28, no. 2, pp. 185–200, 2008. View at Publisher · View at Google Scholar · View at Scopus
  75. G. Niu, K. L. Wright, M. Huang et al., “Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis,” Oncogene, vol. 21, no. 13, pp. 2000–2008, 2002. View at Publisher · View at Google Scholar · View at Scopus
  76. D. Wei, X. Le, L. Zheng et al., “Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis,” Oncogene, vol. 22, no. 3, pp. 319–329, 2003. View at Publisher · View at Google Scholar · View at Scopus
  77. Q. Xu, J. Briggs, S. Park et al., “Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways,” Oncogene, vol. 24, no. 36, pp. 5552–5560, 2005. View at Publisher · View at Google Scholar · View at Scopus
  78. M. Bartoli, D. Platt, T. Lemtalsi et al., “VEGF differentially activates STAT3 in microvascular endothelial cells,” The FASEB, vol. 17, no. 11, pp. 1562–1564, 2003. View at Scopus
  79. Y. Yahata, Y. Shirakata, S. Tokumaru et al., “Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation,” Journal of Biological Chemistry, vol. 278, no. 41, pp. 40026–40031, 2003. View at Publisher · View at Google Scholar · View at Scopus
  80. G. L. Semenza, “Targeting HIF-1 for cancer therapy,” Nature Reviews Cancer, vol. 3, no. 10, pp. 721–732, 2003. View at Scopus
  81. M.-K. Oh, H.-J. Park, N.-H. Kim, S.-J. Park, I.-Y. Park, and I.-S. Kim, “Hypoxia-inducible factor-1α enhances haptoglobin gene expression by improving binding of STAT3 to the promoter,” Journal of Biological Chemistry, vol. 286, no. 11, pp. 8857–8865, 2011. View at Publisher · View at Google Scholar · View at Scopus
  82. B. Groner, P. Lucks, and C. Borghouts, “The function of Stat3 in tumor cells and their microenvironment,” Seminars in Cell and Developmental Biology, vol. 19, no. 4, pp. 341–350, 2008. View at Publisher · View at Google Scholar · View at Scopus
  83. L. Zhang, D. Alizadeh, M. van Handel, M. Kortylewski, H. Yu, and B. Badie, “Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice,” GLIA, vol. 57, no. 13, pp. 1458–1467, 2009. View at Publisher · View at Google Scholar · View at Scopus
  84. A. M. Gamero, H. A. Young, and R. H. Wiltrout, “Inactivation of Stat3 in tumor cells: releasing a brake on immune responses against cancer?” Cancer Cell, vol. 5, no. 2, pp. 111–112, 2004. View at Publisher · View at Google Scholar · View at Scopus
  85. H. Yu, D. Pardoll, and R. Jove, “STATs in cancer inflammation and immunity: a leading role for STAT3,” Nature Reviews Cancer, vol. 9, no. 11, pp. 798–809, 2009. View at Publisher · View at Google Scholar · View at Scopus
  86. W. Zou, “Immunosuppressive networks in the tumour environment and their therapeutic relevance,” Nature Reviews Cancer, vol. 5, no. 4, pp. 263–274, 2005. View at Publisher · View at Google Scholar · View at Scopus
  87. A. P. Vicari, C. Caux, and G. Trinchieri, “Tumour escape from immune surveillance through dendritic cell inactivation,” Seminars in Cancer Biology, vol. 12, no. 1, pp. 33–42, 2002. View at Publisher · View at Google Scholar · View at Scopus
  88. H. Yu, M. Kortylewski, and D. Pardoll, “Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment,” Nature Reviews Immunology, vol. 7, no. 1, pp. 41–51, 2007. View at Publisher · View at Google Scholar · View at Scopus
  89. A. C. Bharti, N. Donato, and B. B. Aggarwal, “Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells,” Journal of Immunology, vol. 171, no. 7, pp. 3863–3871, 2003. View at Scopus
  90. W. Glienke, L. Maute, J. Wicht, and L. Bergmann, “Curcumin inhibits constitutive STAT3 phosphorylation in human pancreatic cancer cell lines and downregulation of Survivin/BIRC5 gene expression,” Cancer Investigation, vol. 28, no. 2, pp. 166–171, 2010. View at Publisher · View at Google Scholar · View at Scopus
  91. G. G. Mackenzie, N. Queisser, M. L. Wolfson, C. G. Fraga, A. M. Adamo, and P. I. Oteiza, “Curcumin induces cell-arrest and apoptosis in association with the inhibition of constitutively active NF-κB and STAT3 pathways in Hodgkin's lymphoma cells,” International Journal of Cancer, vol. 123, no. 1, pp. 56–65, 2008. View at Publisher · View at Google Scholar · View at Scopus
  92. N. Chakravarti, J. N. Myers, and B. B. Aggarwal, “Targeting constitutive and interleukin-6-inducible signal transducers and activators of transcription 3 pathway in head and neck squamous cell carcinoma cells by curcumin (diferuloylmethane),” International Journal of Cancer, vol. 119, no. 6, pp. 1268–1275, 2006. View at Publisher · View at Google Scholar · View at Scopus
  93. S. Uddin, A. R. Hussain, P. S. Manogaran et al., “Curcumin suppresses growth and induces apoptosis in primary effusion lymphoma,” Oncogene, vol. 24, no. 47, pp. 7022–7030, 2005. View at Publisher · View at Google Scholar · View at Scopus
  94. R. Blasius, S. Reuter, E. Henry, M. Dicato, and M. Diederich, “Curcumin regulates signal transducer and activator of transcription (STAT) expression in K562 cells,” Biochemical Pharmacology, vol. 72, no. 11, pp. 1547–1554, 2006. View at Publisher · View at Google Scholar · View at Scopus
  95. J. H. Seo, K. J. Jeong, W. J. Oh et al., “Lysophosphatidic acid induces STAT3 phosphorylation and ovarian cancer cell motility: their inhibition by curcumin,” Cancer Letters, vol. 288, no. 1, pp. 50–56, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. M. A. Bill, J. R. Fuchs, C. Li et al., “The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity,” Molecular Cancer, vol. 9, article 165, 2010. View at Publisher · View at Google Scholar · View at Scopus
  97. M. Jang, L. Cai, G. O. Udeani et al., “Cancer chemopreventive activity of resveratrol, a natural product derived from grapes,” Science, vol. 275, no. 5297, pp. 218–220, 1997. View at Scopus
  98. A. Kotha, M. Sekharam, L. Cilenti et al., “Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein,” Molecular Cancer Therapeutics, vol. 5, no. 3, pp. 621–629, 2006. View at Publisher · View at Google Scholar · View at Scopus
  99. A. Bhardwaj, G. Sethi, S. Vadhan-Raj et al., “Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-κB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells,” Blood, vol. 109, no. 6, pp. 2293–2302, 2007. View at Publisher · View at Google Scholar · View at Scopus
  100. B. S. Wung, M. C. Hsu, C. C. Wu, and C. W. Hsieh, “Resveratrol suppresses IL-6-induced ICAM-1 gene expression in endothelial cells: effects on the inhibition of STAT3 phosphorylation,” Life Sciences, vol. 78, no. 4, pp. 389–397, 2005. View at Publisher · View at Google Scholar · View at Scopus
  101. L.-J. Yu, M.-L. Wu, H. Li et al., “Inhibition of STAT3 expression and signaling in resveratrol-differentiated medulloblastoma cells,” Neoplasia, vol. 10, no. 7, pp. 736–744, 2008. View at Publisher · View at Google Scholar · View at Scopus
  102. Y.-P. Yang, Y.-L. Chang, P.-I. Huang et al., “Resveratrol suppresses tumorigenicity and enhances radiosensitivity in primary glioblastoma tumor initiating cells by inhibiting the STAT3 axis,” Journal of Cellular Physiology, vol. 227, no. 3, pp. 976–993, 2012. View at Publisher · View at Google Scholar · View at Scopus
  103. H. H. Sedlacek, “Mechanisms of action of flavopiridol,” Critical Reviews in Oncology/Hematology, vol. 38, no. 2, pp. 139–170, 2001. View at Publisher · View at Google Scholar · View at Scopus
  104. Y. K. Lee, C. R. Isham, S. H. Kaufman, and K. C. Bible, “Flavopiridol disrupts STAT3/DNA interactions, attenuates STAT3-directed transcription, and combines with the Jak kinase inhibitor AG490 to achieve cytotoxic synergy,” Molecular Cancer Therapeutics, vol. 5, no. 1, pp. 138–148, 2006. View at Publisher · View at Google Scholar · View at Scopus
  105. F. Arguello, M. Alexander, J. A. Sterry et al., “Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity in vivo against human leukemia and lymphoma xenografts,” Blood, vol. 91, no. 7, pp. 2482–2490, 1998. View at Scopus
  106. Y. Dai, M. Rahmani, X.-Y. Pei, P. Dent, and S. Grant, “Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms,” Blood, vol. 104, no. 2, pp. 509–518, 2004. View at Publisher · View at Google Scholar · View at Scopus
  107. Y.-W. Chen, K.-H. Chen, P.-I. Huang et al., “Cucurbitacin I suppressed stem-like property and enhanced radiation-induced apoptosis in head and neck squamous carcinoma-derived CD44+ALDH1+ cells,” Molecular Cancer Therapeutics, vol. 9, no. 11, pp. 2879–2892, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. M. A. Blaskovich, J. Sun, A. Cantor, J. Turkson, R. Jove, and S. M. Sebti, “Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice,” Cancer Research, vol. 63, no. 6, pp. 1270–1279, 2003. View at Scopus
  109. G. B. Iwanski, D. H. Lee, S. En-Gal et al., “Cucurbitacin B, a novel in vivo potentiator of gemcitabine with low toxicity in the treatment of pancreatic cancer,” British Journal of Pharmacology, vol. 160, no. 4, pp. 998–1007, 2010. View at Publisher · View at Google Scholar · View at Scopus
  110. J. Sun, M. A. Blaskovich, R. Jove, S. K. Livingston, D. Coppola, and S. M. Sebti, “Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity,” Oncogene, vol. 24, no. 20, pp. 3236–3245, 2005. View at Publisher · View at Google Scholar · View at Scopus
  111. W.-W. Huang, J.-S. Yang, M.-W. Lin et al., “Cucurbitacin e induces G2/M phase arrest through STAT3/p53/p21 signaling and provokes apoptosis via Fas/CD95 and mitochondria-dependent pathways in human bladder cancer T24 cells,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 952762, 11 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  112. H. Song, R. Wang, S. Wang, and J. Lin, “A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 13, pp. 4700–4705, 2005. View at Publisher · View at Google Scholar · View at Scopus
  113. M. Weidler, J. Rether, T. Anke, and G. Erkel, “Inhibition of interleukin-6 signaling and Stat3 activation by a new class of bioactive cyclopentenone derivatives,” Biochemical and Biophysical Research Communications, vol. 276, no. 2, pp. 447–453, 2000. View at Publisher · View at Google Scholar · View at Scopus
  114. A. Eberhard, A. L. Burlingame, C. Eberhard, G. L. Kenyon, K. H. Nealson, and N. J. Oppenheimer, “Structural identification of autoinducer of Photobacterium fischeri luciferase,” Biochemistry, vol. 20, no. 9, pp. 2444–2449, 1981. View at Scopus
  115. L. Li, D. Hooi, S. R. Chhabra, D. Pritchard, and P. E. Shaw, “Bacterial N-acylhomoserine lactone-induced apoptosis in breast carcinoma cells correlated with down-modulation of STAT3,” Oncogene, vol. 23, no. 28, pp. 4894–4902, 2004. View at Publisher · View at Google Scholar · View at Scopus
  116. R. Hoessel, S. Leclerc, J. A. Endicott et al., “Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases,” Nature Cell Biology, vol. 1, no. 1, pp. 60–67, 1999. View at Scopus
  117. K. H. Merz, S. Schwahn, F. Hippe, S. Mühlbeyer, S. Jakobs, and G. Eisenbrand, “Novel indirubin derivatives, promising anti-tumor agents inhibiting cyclin-dependent kinases,” International Journal of Clinical Pharmacology and Therapeutics, vol. 42, no. 11, pp. 656–658, 2004. View at Scopus
  118. S. Nam, R. Buettner, J. Turkson et al., “Indirubin derivatives inhibit Stat3 signaling and induce apoptosis in human cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 17, pp. 5998–6003, 2005. View at Publisher · View at Google Scholar · View at Scopus
  119. L. Liu, S. Nam, Y. Tian et al., “6-Bromoindirubin-3′-oxime inhibits JAK/STAT3 signaling and induces apoptosis of human melanoma cells,” Cancer Research, vol. 71, no. 11, pp. 3972–3979, 2011. View at Publisher · View at Google Scholar · View at Scopus
  120. Y. Zhen, V. Sørensen, Y. Jin, Z. Suo, and A. Wiȩdłocha, “Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK,” Oncogene, vol. 26, no. 44, pp. 6372–6385, 2007. View at Publisher · View at Google Scholar · View at Scopus
  121. Z. Ni, W. Lou, E. S. Leman, and A. C. Gao, “Inhibition of constitutively activated Stat3 signaling pathway suppresses growth of prostate cancer cells,” Cancer Research, vol. 60, no. 5, pp. 1225–1228, 2000. View at Scopus
  122. J. De Vos, M. Jourdan, K. Tarte, C. Jasmin, and B. Klein, “JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells,” British Journal of Haematology, vol. 109, no. 4, pp. 823–828, 2000. View at Publisher · View at Google Scholar · View at Scopus
  123. D. Kube, U. Holtick, M. Vockerodt et al., “STAT3 is constitutively activated in Hodgkin cell lines,” Blood, vol. 98, no. 3, pp. 762–770, 2001. View at Publisher · View at Google Scholar · View at Scopus
  124. M. Nielsen, K. Kaltoft, M. Nordahl et al., “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,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 13, pp. 6764–6769, 1997. View at Publisher · View at Google Scholar · View at Scopus
  125. U. Holtick, M. Vockerodt, D. Pinkert et al., “STAT3 is essential for Hodgkin lymphoma cell proliferation and is a target of tyrphostin AG17 which confers sensitization for apoptosis,” Leukemia, vol. 19, no. 6, pp. 936–944, 2005. View at Publisher · View at Google Scholar · View at Scopus
  126. S. Verstovsek, H. Kantarjian, R. A. Mesa et al., “Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis,” The New England Journal of Medicine, vol. 363, no. 12, pp. 1117–1127, 2010. View at Publisher · View at Google Scholar · View at Scopus
  127. A. Quintás-Cardama, H. Kantarjian, J. Cortes, and S. Verstovsek, “Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond,” Nature Reviews Drug Discovery, vol. 10, no. 2, pp. 127–140, 2011. View at Publisher · View at Google Scholar · View at Scopus
  128. S. . Verstovsek, C. Machida, J. P. Dean, and H. Myint, “Pacritinib. Inhibitor of tyrosine-protein kinase JAK2, inhibitor of FLT-3, treatment of myelofibrosis,” Drugs of the Future, vol. 38, no. 6, pp. 375–386, 2013.
  129. M. Hedvat, D. Huszar, A. Herrmann et al., “The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors,” Cancer Cell, vol. 16, no. 6, pp. 487–497, 2009. View at Publisher · View at Google Scholar · View at Scopus
  130. C. Houssier, M. C. Depauw-Gillet, R. Hacha, and E. Fredericq, “Alteration in the nucleosome and chromatin structures upon interaction with platinum coordination complexes,” Biochimica et Biophysica Acta, vol. 739, no. 3, pp. 317–325, 1983. View at Publisher · View at Google Scholar · View at Scopus
  131. J. Deng, F. Grande, and N. Neamati, “Small molecule inhibitors of Stat3 signaling pathway,” Current Cancer Drug Targets, vol. 7, no. 1, pp. 91–107, 2007. View at Publisher · View at Google Scholar · View at Scopus
  132. H. Song, V. K. Sondak, D. L. Barber, T. J. Reid, and J. Lin, “Modulation of Janus kinase 2 by cisplatin in cancer cells,” International journal of oncology, vol. 24, no. 4, pp. 1017–1026, 2004. View at Scopus
  133. J. Turkson, S. Zhang, J. Palmer et al., “Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity,” Molecular Cancer Therapeutics, vol. 3, no. 12, pp. 1533–1542, 2004. View at Scopus
  134. J. Turkson, S. Zhang, L. B. Mora, A. Burns, S. Sebti, and R. Jove, “A novel platinum compound inhibits constitutive Stat3 signaling and induces cell cycle arrest and apoptosis of malignant cells,” Journal of Biological Chemistry, vol. 280, no. 38, pp. 32979–32988, 2005. View at Publisher · View at Google Scholar · View at Scopus
  135. S. R. Choudhari, M. A. Khan, G. Harris et al., “Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent, Atiprimod,” Molecular Cancer Therapeutics, vol. 6, no. 1, pp. 112–121, 2007. View at Publisher · View at Google Scholar · View at Scopus
  136. M. Amit-Vazina, S. Shishodia, D. Harris et al., “Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells,” British Journal of Cancer, vol. 93, no. 1, pp. 70–80, 2005. View at Publisher · View at Google Scholar · View at Scopus
  137. M. Wang, L. Zhang, X. Han et al., “Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways,” Blood, vol. 109, no. 12, pp. 5455–5462, 2007. View at Publisher · View at Google Scholar · View at Scopus
  138. S. Faderl, A. Ferrajoli, D. Harris, Q. Van, H. M. Kantarjian, and Z. Estrov, “Atiprimod blocks phosphorylation of JAK-STAT and inhibits proliferation of acute myeloid leukemia (AML) cells,” Leukemia Research, vol. 31, no. 1, pp. 91–95, 2007. View at Publisher · View at Google Scholar · View at Scopus
  139. J. E. Frampton and R. N. Brogden, “Pentoxifylline (oxpentifylline). A review of its therapeutic efficacy in the management of peripheral vascular and cerebrovascular disorders,” Drugs & Aging, vol. 7, no. 6, pp. 480–503, 1995. View at Scopus
  140. M. Z. . Kamran and R. P. Gude, “Preclinical evaluation of the antimetastatic efficacy of Pentoxifylline on A375 human melanoma cell line,” Biomedicine & Pharmacotherapy, vol. 66, no. 8, pp. 617–626, 2012.
  141. M. Z. . Kamran and R. P. Gude, “Pentoxifylline inhibits melanoma tumor growth and angiogenesis by targeting STAT3 signaling pathway,” Biomedicine & Pharmacotherapy, vol. 67, no. 5, pp. 399–405, 2013.
  142. P. L. Leong, G. A. Andrews, D. E. Johnson et al., “Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 7, pp. 4138–4143, 2003. View at Publisher · View at Google Scholar · View at Scopus
  143. S. Xi, W. E. Gooding, and J. R. Grandis, “In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy,” Oncogene, vol. 24, no. 6, pp. 970–979, 2005. View at Publisher · View at Google Scholar · View at Scopus
  144. M. Sen, S. M. Thomas, S. Kim et al., “First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy,” Cancer Discovery, vol. 2, no. 8, pp. 694–705, 2012.
  145. X. Zhang, J. Zhang, L. Wang, H. Wei, and Z. Tian, “Therapeutic effects of STAT3 decoy oligodeoxynucleotide on human lung cancer in xenograft mice,” BMC Cancer, vol. 7, article 149, 2007. View at Publisher · View at Google Scholar · View at Scopus
  146. J. Shen, R. Li, and G. Li, “Inhibitory effects of decoy-ODN targeting activated STAT3 on human glioma growth in vivo,” In Vivo, vol. 23, no. 2, pp. 237–243, 2009. View at Scopus