STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (Review)

  • Authors:
    • Xiaochun Wang
    • Philip J. Crowe
    • David Goldstein
    • Jia-Lin Yang
  • View Affiliations

  • Published online on: July 24, 2012     https://doi.org/10.3892/ijo.2012.1568
  • Pages: 1181-1191
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Signal transducer and activator of transcription 3 (STAT3) regulates many critical functions in human normal and malignant tissues, such as differentiation, proliferation, survival, angiogenesis and immune function. Constitutive activation of STAT3 is implicated in a wide range of human cancers. As such, STAT3 has been studied as a tumour therapeutic target. This review aimed principally to summarise the updated research on STAT3 inhibition studies and their therapeutic potential in solid tumours. Recent literature associated with STAT3 inhibition was reviewed through PubMed and Medline database, followed by critical comparison and analysis. Constitutive activation of STAT3 has been identified as abnormal and oncogenic. The pathway of STAT3 activation and signal transduction identifies 3 approaches for inhibition: modulating upstream positive or negative regulators, regulating RNA (DN-STAT3, anti-sense RNA, siRNA and microRNA) or targeting STAT3 protein at different domains. The last approach using small molecule STAT3 inhibitors has been the most examined so far with both preclinical and clinical studies. Targeting STAT3 using a specific inhibitor may be a useful cancer treatment approach, with the potential for a broad clinical impact.

References

1 

Darnell JE: Transcription factors as targets for cancer therapy. Nat Rev Cancer. 2:740–749. 2002. View Article : Google Scholar : PubMed/NCBI

2 

Darnell JE: STATs and gene regulation. Science. 277:1630–1635. 1997. View Article : Google Scholar : PubMed/NCBI

3 

Bromberg J and Darnell JE: The role of STATs in transcriptional control and their impact on cellular function. Oncogene. 19:2468–2473. 2000. View Article : Google Scholar : PubMed/NCBI

4 

Ihle JN: STATs: signal transducers and activators of transcription. Cell. 84:331–334. 1996. View Article : Google Scholar : PubMed/NCBI

5 

Herrington J, Smit LS, Schwartz J and Carter-Su C: The role of STAT proteins in growth hormone signaling. Oncogene. 19:2585–2597. 2000. View Article : Google Scholar : PubMed/NCBI

6 

Alvarez JV, Greulich H, Sellers WR, Meyerson M and Frank DA: Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor. Cancer Res. 66:3162–3168. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Yin W, Cheepala S, Roberts JN, Syson-Chan K, DiGiovanni J and Clifford JL: Active Stat3 is required for survival of human squamous cell carcimoma cells in serum-free conditions. Mol Cancer. 5:152006. View Article : Google Scholar : PubMed/NCBI

8 

Kusaba T, Nakayama T, Yamazumi K, et al: Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rep. 15:1445–1451. 2006.PubMed/NCBI

9 

Morikawa T, Baba Y, Yamauchi M, et al: STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers. Clin Cancer Res. 17:1452–1462. 2011. View Article : Google Scholar : PubMed/NCBI

10 

de la Iglesia N, Konopka G, Lim KL, et al: Deregulation of a STAT3-interleukin 8 signaling pathway promotes human glioblastoma cell proliferation and invasiveness. J Neurosci. 28:5870–5878. 2008.PubMed/NCBI

11 

de la Iglesia N, Konopka G, Puram SV, et al: Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev. 22:449–462. 2008.PubMed/NCBI

12 

Copeland NG, Gilbert DJ, Schindler C, et al: Distribution of the mammalian Stat gene family in mouse chromosomes. Genomics. 29:225–228. 1995. View Article : Google Scholar : PubMed/NCBI

13 

Lai SY and Johnson FM: Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: implications for future therapeutic approaches. Drug Resist Updat. 13:67–78. 2010. View Article : Google Scholar : PubMed/NCBI

14 

Quesnelle KM, Boehm AL and Grandis JR: STAT-mediated EGFR signaling in cancer. J Cell Biochem. 102:311–319. 2007. View Article : Google Scholar : PubMed/NCBI

15 

Gao L, Zhang L, Hu J, et al: Down-regulation of signal transducer and activator of transcription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo. Clin Cancer Res. 11:6333–6341. 2005. View Article : Google Scholar : PubMed/NCBI

16 

Kisseleva T, Bhattacharya S, Braunstein J and Schindler CW: Sigaling through the JAK-STAT pathway, recent advances and future challenges. Gene. 285:1–24. 2002. View Article : Google Scholar : PubMed/NCBI

17 

Aggarwal BB, Kunnumakkara AB, Harikumar KB, et al: Signal tansducer and activator of transcription-3, inflammation, and cancer. Ann NY Acad Sci. 1171:59–76. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Pawson T, Gish GD and Nash P: SH2 domains, interaction modules and cellular wiring. Trends Cell Biol. 11:504–511. 2001. View Article : Google Scholar : PubMed/NCBI

19 

Zhong Z, Wen Z and Darnell JE: Stat3, a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 264:95–98. 1994. View Article : Google Scholar : PubMed/NCBI

20 

Leeman R, Lui VWY and Grandis JR: STAT3 as a therapeutic target in head and neck cancer. Expert Opin Biol Ther. 6:231–241. 2006. View Article : Google Scholar : PubMed/NCBI

21 

Takeda K, Noguchi K, Shi W, et al: Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci USA. 94:3801–3804. 1997. View Article : Google Scholar : PubMed/NCBI

22 

Yang XO, Panopoulos AD, Nurieva R, et al: STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 282:9358–9363. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Miyoshi K, Takaishi M, Nakajima K, et al: Stat3 as a therapeutic target for the treatment of psoriasis: a clinical feasibility study with STA-21, a Stat3 inhibitor. J Invest Dermatol. 131:108–117. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Zhang HY, Zhang Q, Zhang X, et al: Cancer-related inflammation and Barrett’s carcinogenesis: interleukin-6 and STAT3 mediate apoptotic resistance in transformed Barrett’s cells. Am J Physiol Gastrointest Liver Physiol. 300:G454–G460. 2011.

25 

Mora LB, Buettner R, Seigne J, et al: Constitutive activation of Atat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res. 62:6659–6666. 2002.PubMed/NCBI

26 

Burger R, Le Gouill S, Tai Y-T, et al: Janus kinase inhibitor INCB20 has antiproliferative and apoptotic effects on human myeloma cells in vitro and in vivo. Mol Cancer Ther. 8:26–35. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Wei L-H, Kuo M-L, Chen C-A, et al: Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene. 22:1517–1527. 2003. View Article : Google Scholar : PubMed/NCBI

28 

Lopiccolo J, Blumenthal G, Bernstein WB and Dennis PA: Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat. 11:32–50. 2008. View Article : Google Scholar : PubMed/NCBI

29 

Sasse J, Hemmann U, Schwartz C, et al: Mutational analysis of acute-phase response factor/Stat3 activation and dimerization. Mol Cell Biol. 17:4677–4686. 1997.PubMed/NCBI

30 

Shuai K, Horvath CM, Huang LHT, Qureshi S, Cowburn D and Darnell JE: Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell. 76:821–828. 1994. View Article : Google Scholar : PubMed/NCBI

31 

Fletcher S and Gunning PT: Mild, efficient and rapid O-debenzylation of ortho-substituted phenols with trifluoroacetic acid. Tetrahedron Lett. 49:4817–4819. 2008. View Article : Google Scholar

32 

Yu C-L, Meyer DJ, Campbell GS, et al: Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science. 269:81–83. 1995. View Article : Google Scholar : PubMed/NCBI

33 

Smithgall TE, Briggs SD, Schreiner S, Lerner EC, Cheng H and Wilson MB: Control of myeloid differentiation and survial by Stats. Oncogene. 19:2612–2618. 2000. View Article : Google Scholar : PubMed/NCBI

34 

Bowman T, Garcia R, Turkson J and Jove R: STATs in oncogenesis. Oncogene. 19:2474–2488. 2000. View Article : Google Scholar : PubMed/NCBI

35 

Catlett-Falcone R, Dalton WS and Jove R: STAT proteins as novel targets for cancer therapy. Curr Opin Oncol. 11:490–496. 1999. View Article : Google Scholar : PubMed/NCBI

36 

Inamura K, Matsuzaki Y, Uematsu N, Hondab A, Tanaka N and Uchida K: Rapid inhibition of MAPK signaling and anti-proliferation effect via JAK/STAT signaling by interferon-alpha in hepatocellular carcinoma cell lines. Biochim Biophys Acta. 1745:401–410. 2005. View Article : Google Scholar : PubMed/NCBI

37 

Yang JL, Zahorowska B, Kasim Y, Goldstein D and Crowe P: Mechanism of the synergistic antiproliferative effect of gefitinib and interferon-alpha in sarcoma cell lines. Proc 101st Ann Meet AACR. 398–399:(abs. 1655). 2010.

38 

Turkson J and Jove R: STAT proteins: novel molecular targets for cancer drug discovery. Oncogene. 19:6613–6626. 2000. View Article : Google Scholar : PubMed/NCBI

39 

Yu H and Jove R: The STATs of cancer - new molecular targets come of age. Nat Rev Cancer. 4:97–105. 2004. View Article : Google Scholar : PubMed/NCBI

40 

Aggarwal BB, Sethi G, Ahn KS, et al: Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer. Ann NY Acad Sci. 1091:151–169. 2006. View Article : Google Scholar : PubMed/NCBI

41 

Jaganathan S, Yue P, Paladino DC, Bogdanovic J, Huo Q and Turkson J: A functional nuclear epidermal growth factor receptor, Src and Stat3 heteromeric complex in pancreatic cancer cells. PLoS One. 6:e196052011. View Article : Google Scholar : PubMed/NCBI

42 

Arany I, Chen S-H, Megyesi JK, et al: Differentiation-dependent expression of signal transducers and activators of transcription (STATs) might modify responses to growth factors in the cancers of the head and neck. Cancer Lett. 199:83–89. 2003. View Article : Google Scholar

43 

Masuda M, Suzui M, Yasumatu R, et al: Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res. 62:3351–3355. 2002.PubMed/NCBI

44 

Chun K-S and Langenbach R: The prostaglandin E2 receptor, EP2, regulates survivin expression via an EGFR/STAT3 pathway in UVB-exposed mouse skin. Mol Carcinog. 50:439–448. 2011. View Article : Google Scholar : PubMed/NCBI

45 

Grandis JR, Drenning SD, Zeng Q, et al: Contitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci USA. 97:4227–4232. 2000. View Article : Google Scholar : PubMed/NCBI

46 

Kijima T, Niwa H, Steinman RA, et al: STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo. Cell Growth Differ. 13:355–362. 2002.PubMed/NCBI

47 

Huang M, Page C, Reynolds K and Lin J: Constitutive activation of Stat 3 oncogene product in human ovarian carcinoma cells. Gynecol Oncol. 79:67–73. 2000. View Article : Google Scholar : PubMed/NCBI

48 

Niu G, Bowman T, HUang M, et al: Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene. 21:7001–7010. 2002. View Article : Google Scholar : PubMed/NCBI

49 

Chen CL, Hsieh FC, Lieblein JC, et al: Stat3 activation in human endometrial and cervical cancers. Br J Cancer. 96:591–599. 2007. View Article : Google Scholar : PubMed/NCBI

50 

Van der Fits L, van Kester MS, Qin Y, et al: MicroRNA-21 expression in CD4+ T cells is regulated by STAT3 and is pathologically involved in Sézary Syndrome. J Invest Dermatol. 131:762–768. 2010.PubMed/NCBI

51 

Loffler D, Brocke-Heidrich K, Pfeifer G, et al: Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood. 110:1330–1333. 2007. View Article : Google Scholar : PubMed/NCBI

52 

Ahluwalia A, Busse BA, Thiruvengadam SS and Tarnawski AS: Importins are critical for colorectal cancer (CRC) growth a nd are novel biomarkers of CRC. Underlying mechanisms include: increased nuclear transport of P-CREB and p-STAT3, VEGF gene promoter activation and aberrant VEGF expression. Gastroenterology. 140:S1842011.

53 

Wei D, Le X, Zheng L, et al: Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene. 22:319–329. 2003. View Article : Google Scholar : PubMed/NCBI

54 

Xu Q, Briggs J, Park S, et al: Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene. 24:5552–5560. 2005. View Article : Google Scholar : PubMed/NCBI

55 

Xie T-X, Wei D, Liu M, et al: Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene. 23:3550–3560. 2004. View Article : Google Scholar : PubMed/NCBI

56 

Dechow TN, Pedranzini L, Leitch A, et al: Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc Natl Acad Sci USA. 101:10602–10607. 2004. View Article : Google Scholar : PubMed/NCBI

57 

Yu H, Kortylewski M and Pardoll D: Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Immunology. 7:41–51. 2007.PubMed/NCBI

58 

Kortylewski M, Kujawski M, Wang T, et al: Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 11:1314–1321. 2005. View Article : Google Scholar : PubMed/NCBI

59 

Kortylewski M and Yu H: Role of Stat3 in suppressing anti-tumor immunity. Curr Opin Immunol. 20:228–233. 2008. View Article : Google Scholar : PubMed/NCBI

60 

Wang T, Niu G, Kortylewski M, et al: Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 10:48–54. 2004. View Article : Google Scholar : PubMed/NCBI

61 

Garcia R, Bowman TL, Niu G, et al: Constitutive activation of STAT3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene. 20:2499–2513. 2001. View Article : Google Scholar : PubMed/NCBI

62 

Nagpal JK, Mishra R and Das BR: Activation of Stat-3 as one of the early events in tobacco chewing-mediated oral carcinogenesis. Cancer. 94:2393–2400. 2002. View Article : Google Scholar : PubMed/NCBI

63 

Deng J-Y, Sun D, Liu X-Y, Pan Y and Liang H: STAT-3 correlates with lymph node metastasis and cell survival in gastric cancer. World J Gastroenterol. 16:5380–5387. 2010. View Article : Google Scholar : PubMed/NCBI

64 

Watson CJ and Miller WR: Elevated levels of members of the STAT family of transcription factors in breast carcinoma nuclear extracts. Br J Cancer. 71:840–844. 1995. View Article : Google Scholar : PubMed/NCBI

65 

Kosaka T, Yamaki E, Mogi A and Kuwano H: Mechanisms of resistance to EGFR TKIs and development of a new generation of drugs in non-small-cell lung cancer. J Biomed Biotechnol. 2011:1–7. 2011. View Article : Google Scholar : PubMed/NCBI

66 

Himpe E and Kooijman R: Insulin-like growth factor-I receptor signal transduction and the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Biofactors. 35:76–81. 2009. View Article : Google Scholar : PubMed/NCBI

67 

Sporeno E, Savino R, Ciapponi L, et al: Human interleukin-6 receptor super-antagonists with high potency and wide spectrum on multiple myeloma cells. Blood. 87:4510–4519. 1996.PubMed/NCBI

68 

Demartis A, Bernassola F, Savino R, Melino G and Ciliberto G: Interleukin 6 receptor superantagonists are potent inducers of human multiple. Cancer Res. 56:4213–4218. 1996.PubMed/NCBI

69 

Catlett-Falcone R, Landowski TH, Oshiro MM, et al: Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity. 10:105–115. 1999. View Article : Google Scholar : PubMed/NCBI

70 

Johnson FM, Saigal B, Talpaz M and Donato NJ: Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res. 11:6924–6932. 2005. View Article : Google Scholar : PubMed/NCBI

71 

Perry E, Tsruya R, Levitsky P, et al: TMF/ARA160 is a BC-box-containing protein that mediates the degradation of Stat3. Oncogene. 23:8908–8919. 2004. View Article : Google Scholar : PubMed/NCBI

72 

Gu Q, Kong Y, Yu Z-B, Bai L and Xiao Y-B: Hypoxia-induced SOCS3 is limiting STAT3 phosphorylation and NF-κB activation in congenital heart disease. Biochimie. 93:909–920. 2011.PubMed/NCBI

73 

Ulane CM, Kentsis A, Cruz CD, Parisien J-P, Schneider KL and Horvath CM: Composition and assembly of STAT-targeting ubiquitin ligase complexes: paramyxovirus V protein carboxyl terminus is an oligomerization domain. J Virol. 79:10180–10189. 2005. View Article : Google Scholar

74 

Lesina M, Kurkowski Magdalena U, Ludes K, et al: Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic Cancer. Cancer Cell. 19:456–469. 2011. View Article : Google Scholar

75 

Lindemann C, Hackmann O, Delic S, Schmidt N, Reifenberger G and Riemenschneider MJ: SOCS3 promoter methylation methylation is mutually exclusive to EGFR amplification in gliomas and promotes glioma cell invasion through STAT3 and FAK activation. Acta Neuropathol. 122:241–251. 2011. View Article : Google Scholar : PubMed/NCBI

76 

Kluge A, Dabir S, Vlassenbroeck I, Eisenberg R and Dowlati A: Protein inhibitor of activated STAT3 expression in lung cancer. Mol Oncol. 5:256–264. 2011. View Article : Google Scholar : PubMed/NCBI

77 

Migone T-S, Cacalano NA, Taylor N, Yi T, Waldmann TA and Johnston JA: Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 recepto; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells. Proc Natl Acad Sci USA. 95:3845–3850. 1998. View Article : Google Scholar : PubMed/NCBI

78 

Schaper F, Gendo C, ECK M, et al: Activation of the protein tyrosine phosphatease SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine Jak1 and limits acute-phase protein expression. Biochem J. 355:557–565. 1998.

79 

Irie-Sasaki J, Sasaki T, Matsumoto W, et al: CD45 is a JAK phosphatase and negatively regulates cytokine recptor signalling. Nature. 409:349–354. 2001. View Article : Google Scholar : PubMed/NCBI

80 

Sun S and Steinberg BM: PTEN is a negative regualtor of STAT3 activation in human papillomavirus-infected cells. J Gen Virol. 83:1651–1658. 2002.PubMed/NCBI

81 

Desrivières S, Kunz C, Barash I, Vafaizadeh V, Borghouts C and Groner B: The biological functions of the versatile transcription factors STAT3 and STAT5 and new strategies for their targeted inhibition. J Mammary Gland Biol Neoplasia. 11:75–87. 2006.PubMed/NCBI

82 

Scoles DR, Nguyen VD, Qin Y, et al: Neurofibromatosis 2 (NF2) tumor suppressor schwannomin and its interacting protein HRS regulate STAT singling. Hum Mol Genet. 11:3179–3189. 2002. View Article : Google Scholar : PubMed/NCBI

83 

Bhasin D, Cisek K, Pandharkar T, et al: Design, synthesis, and studies of small molecule STAT3 inhibitors. Bioorg Med Chem Lett. 18:391–395. 2008. View Article : Google Scholar : PubMed/NCBI

84 

Esquela-Kerscher A and Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar

85 

Akao Y, Nakagawa Y and Naoe T: let-7 MicroRNA functions as a potential grwoth suppressor in human colon cancer cells. Biol Pharm Bull. 29:903–906. 2006. View Article : Google Scholar : PubMed/NCBI

86 

Chan JA, Krichevsky AM and Kosik KS: MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65:6029–6033. 2005. View Article : Google Scholar : PubMed/NCBI

87 

Takamizawa J, Konishi H, Yanagisawa K, et al: Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 64:3753–3756. 2004. View Article : Google Scholar : PubMed/NCBI

88 

Yanaihara N, Caplen N, Bowman E, et al: Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 9:189–198. 2006. View Article : Google Scholar : PubMed/NCBI

89 

Johnson SM, Grosshans H, Shingara J, et al: RAS is regulated by the let-7 microRNA family. Cell. 120:635–647. 2005. View Article : Google Scholar : PubMed/NCBI

90 

He L, Thomson JM, Hemann MT, et al: A microRNA polycistron as a potential human oncogene. Nature. 435:828–833. 2005. View Article : Google Scholar : PubMed/NCBI

91 

Foshay KM and Gallicano GI: miR-17 family miRNAs are expressed during early mammalian development and regulate stem cell differentiation. Dev Biol. 326:431–443. 2009. View Article : Google Scholar : PubMed/NCBI

92 

Krichevsky AM, Sonntag K-C, Isacson O and Kosik KS: Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells. 24:857–864. 2006. View Article : Google Scholar : PubMed/NCBI

93 

Meng F, Henson R, Wehbe-Janek H, Smith H, Ueno Y and Patel T: The microRNA let-7a modulates interleukin-6-dependent STAT-3 survival signaling in malignant human cholangiocytes. J Biol Chem. 282:8256–8264. 2007. View Article : Google Scholar : PubMed/NCBI

94 

Niu G, Heller R, Catlett-Falcone R, et al: Gene therapy with dominant-negative Stat3 suprresses growth of the murine melanoma B16 tumor in vivo. Cancer Res. 59:5059–5063. 1999.PubMed/NCBI

95 

Niu G, Shain KH, Huang M, et al: Overexpression of a dominant-negative signal transducer and activator of trnascription 3 varian in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest. Cancer Res. 61:3276–3280. 2001.PubMed/NCBI

96 

Mishra PJ and Merlino G: MicroRNA reexpression as differentiation therapy in cancer. J Clin Invest. 119:2119–2123. 2009.PubMed/NCBI

97 

Liang Z-W, Guo B-F, Li Y, et al: Plasmid-based Stat3 siRNA delivered by hydroxyapatite nanoparticles suppresses mouse prostate tumour growth in vivo. Asian J Androl. 13:481–486. 2011. View Article : Google Scholar : PubMed/NCBI

98 

Petrocca F and Lieberman J: Promise and chanllenge of RNA interference-based therapy for cancer. J Clin Oncol. 29:747–754. 2011. View Article : Google Scholar : PubMed/NCBI

99 

Fletcher S, Drewry JA, Shahani VM, Page BDG and Gunning PT: Molecular disruption of oncogenic signal transducer and activator of transcription 3 (STAT3) protein. Biochem Cell Biol. 87:825–833. 2009. View Article : Google Scholar : PubMed/NCBI

100 

Turkson J, Ryan D, Kim JS, et al: Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. J Biol Chem. 276:45443–45455. 2001. View Article : Google Scholar : PubMed/NCBI

101 

Turkson J, Kim JS, Zhang S, et al: Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol Cancer Ther. 3:261–269. 2004.PubMed/NCBI

102 

Siddiquee K, Zhang S, Guida WC, et al: Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci USA. 104:7391–7396. 2007. View Article : Google Scholar

103 

Lin L, Amin R, Gallicano GI, et al: The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling. Oncogene. 28:961–972. 2009.PubMed/NCBI

104 

Hayakawa F, Sugimoto K, Kurahashi S, et al: A novel direct STAT3 inhibitor OPB-31121 induces tumor-specific growth inhibition in a wide4 range of hematopoietic malignacies and effectively suppresses the chemotherapy resistant quiescent cell in vivo. 52nd ASH Ann Meet & Expo III-56. 2010

105 

Lo H-W, Cao X, Zhu H and Ali-Osman F: Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and akylators. Clin Cancer Res. 14:6042–6054. 2008. View Article : Google Scholar : PubMed/NCBI

106 

Real PJ, Sierra A, De Juan A, Segovia JC, Lopez-Vega JM and Fernandez-Luna JL: Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene. 21:7611–7618. 2002. View Article : Google Scholar : PubMed/NCBI

107 

Oh D, Han S, Kim TM, et al: A phase I, open-label, nonrandomized trial of OPB-31121, a STAT3 inhibitor, in patients with advanced solid tumors. J Clin Oncol. 28:e130562010.

108 

Sartor CI, Dziubinski ML, Yu C-L, Jove R and Ethier SP: Role of epidermal growth factor receptor and STAT-3 activation in autonomous proliferation of SUM-102PT human breast cancer cells. Cancer Res. 57:978–987. 1997.PubMed/NCBI

109 

Garcia R, Yu C-L, Hudnall A, et al: Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ. 8:1267–1276. 1997.PubMed/NCBI

110 

Song L, Turkson J, Karras JG, Jove R and Haura EB: Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene. 22:4150–4165. 2003. View Article : Google Scholar : PubMed/NCBI

111 

Haura EB, Zheng Z, Song L, Cantor A and Bepler G: Activated epidermal growth factor receptor-Stat-3 signaling promotes tumor survival in vivo in non-small cell lung cancer. Clin Cancer Res. 11:8288–8294. 2005. View Article : Google Scholar : PubMed/NCBI

112 

Gao SP, Mark KG, Leslie K, et al: Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest. 117:3846–3856. 2007. View Article : Google Scholar : PubMed/NCBI

113 

Pfeiffer M, Hartmann T, Leick M, Catusse J, Schmitt-Graeff A and Burger M: Alternative implication of CXCR4 in JAK2/STAT3 activation in small cell lung cancer. Br J Cancer. 100:1949–1956. 2009. View Article : Google Scholar : PubMed/NCBI

114 

Quintanilla-Martinez L, Kremer M, Specht K, et al: Analysis of signal transducer and activator of transcription 3 (Stat3) pathway in multiple myeloma, Stat3 activation and cyclin D1 dysregulation are mutually exclusive events. Am J Pathol. 162:1449–1461. 2003. View Article : Google Scholar : PubMed/NCBI

115 

Chen C-L, Loy A, Cen L, et al: Signal transducer and activator of transcription 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells. BMC Cancer. 7:1112007. View Article : Google Scholar : PubMed/NCBI

116 

Grandis JR, Drenning SD, Chakraborty A, et al: Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor-mediated cell growth in vitro. J Clin Invest. 102:1385–1392. 1998. View Article : Google Scholar : PubMed/NCBI

117 

Grandis JR, Zeng Q and Drenning SD: Epidermal growth factor receptor-mediated Stat3 singaling blocks apoptosis in head and neck cancer. Laryngoscope. 110:868–874. 2000. View Article : Google Scholar : PubMed/NCBI

118 

Sriuranpong V, Park JI, Amornphimoltham P, Patel V, Nelkin BD and Gutkind JS: Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcimoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130. Cancer Res. 63:2948–2956. 2003.

119 

Ni Z, Lou W, Leman ES and Gao AC: Inhibition of constitutively activated Stat3 signaling pathway suppresses growth of prostate cancer cells. Cancer Res. 60:1225–1228. 2000.PubMed/NCBI

120 

Barton BE, Murphy TF, Adem P, Watson RA, Irwin RJ and Huang HF: IL-6 signaling by STAT3 participates in the change from hyperplasia to neoplasia in NRP-152 and NRP-154 rat prostatic epithelial cells. BMC Cancer. 1:192001. View Article : Google Scholar : PubMed/NCBI

121 

DeMiguel F, Lee SO, Lou W, et al: Stat3 enhances the growth of LNCaP human prostate cancer cells in intact and castrated male nude mice. Prostate. 52:123–129. 2002. View Article : Google Scholar : PubMed/NCBI

122 

Barton BE, Karras JG, Murphy TF, Barton A and Huang HF-S: Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: direct STAT3 inhibition induces apoptosis in prostate cancer lines. Mol Cancer Ther. 3:11–20. 2004. View Article : Google Scholar : PubMed/NCBI

123 

Sanchez A, Nagy P and Thorgeirsson SS: STAT-3 activity in chemically-induced hepatocellular carcinoma. Eur J Cancer. 39:2093–2098. 2003. View Article : Google Scholar : PubMed/NCBI

124 

Dhir R, Ni Z, Lou W, De Miguel F, Grandis JR and Gao AC: Stat3 activation in prostatic carcinomas. Prostate. 51:241–246. 2002. View Article : Google Scholar : PubMed/NCBI

125 

Sachez-Ceja SG, Reyes-Maldonado E, Vazquez-Manriquez ME, Lopez-Luna JJ, Belmont A and Gutierrez-Castellanos S: Differential expression of STAT5 and Bcl-xL, and high expression of Neu and STAT3 in non-small-cell lung carcinoma. Lung Cancer. 54:163–168. 2006.PubMed/NCBI

126 

David D, Rajappan LM, Balachandran K, Thulaseedharan JV, Nair AS and Pillai RM: Prognostic significance of STAT3 and phosphorylated STAT3 in human soft tissue tumors - a clinicopathological analysis. J Exp Clin Cancer Res. 30:562011. View Article : Google Scholar : PubMed/NCBI

127 

Niu G, Wright KL, Huang M, et al: Constitutive STAT3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 21:2000–2008. 2002. View Article : Google Scholar : PubMed/NCBI

128 

Gritsko T, Williams A, Turkson J, et al: Persistent activation of Stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res. 12:11–19. 2006. View Article : Google Scholar : PubMed/NCBI

129 

Gao L, Li F, Dong B, et al: Inhibition of STAT3 and ErbB2 suppresses tumor growth, enhances radiosensitivity, and induces mitochondria-dependent apoptosis in glioma cells. Intl J Radiat Oncol Biol Phys. 77:1223–1231. 2010. View Article : Google Scholar : PubMed/NCBI

130 

Song H, Wang R, Wang S and Lin J: A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. Proc Natl Acad Sci USA. 102:4700–4705. 2005. View Article : Google Scholar : PubMed/NCBI

131 

Fuh B, Sobo M, Cen L, et al: LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model. Br J Cancer. 100:106–112. 2009. View Article : Google Scholar : PubMed/NCBI

132 

Schust J, Sperl B, Hollis A, Mayer TU and Berg T: Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 13:1235–1242. 2006. View Article : Google Scholar : PubMed/NCBI

133 

Zhang X, Yue P, Fletcher S, Zhao W, Gunning PT and Turkson J: A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes. Biochem Pharmacol. 79:1398–1409. 2010. View Article : Google Scholar : PubMed/NCBI

134 

Fletcher S, Singh J, Zhang X, et al: Disruption of transcriptionally active Stat3 dimers with non-phosphorylated, salicylic acid-based small molecules: potent in vitro and tumor cell activities. Chem Biol Chem. 10:1959–1964. 2009. View Article : Google Scholar

135 

Siddiquee KAZ, Gunning PT, Glenn M, et al: An oxazole-based small-molecule Stat3 inhibitor modulates Stat3 stability and processing and incuces antitumor cell effects. ACS Chem Biol. 2:787–798. 2007. View Article : Google Scholar : PubMed/NCBI

136 

Uehara Y, Mochizuki M, Matsuno K, Haino T and Asai A: Novel high-throughput screening system for identifying STAT3-SH2 antagonists. Biochem Biophys Res Commun. 380:627–631. 2009. View Article : Google Scholar : PubMed/NCBI

137 

Ball S, Li C, Li P-K and Lin J: The small molecule, LLL12, inhibits STAT3 phosphorylation and induces apoptosis in medulloblastoma and glioblastoma cells. PLoS One. 6:e188202011. View Article : Google Scholar : PubMed/NCBI

138 

Lin L, Hutzen B, Li P-K, et al: A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activites and exhibits potent growth-suppressive activity in human cancer cells. Neoplasia. 12:39–50. 2010.PubMed/NCBI

139 

Matsuno K, Masuda Y, Uehara Y, et al: Identification of a new series of STAT3 inhibitors by virtual screening. ACS Med Chem Lett. 1:371–375. 2010. View Article : Google Scholar : PubMed/NCBI

140 

Ashizawa T, Miyata H, Ishii H, et al: Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation. Int J Oncol. 38:1245–1252. 2011.PubMed/NCBI

Related Articles

Journal Cover

October 2012
Volume 41 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Wang, X., Crowe, P.J., Goldstein, D., & Yang, J. (2012). STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (Review). International Journal of Oncology, 41, 1181-1191. https://doi.org/10.3892/ijo.2012.1568
MLA
Wang, X., Crowe, P. J., Goldstein, D., Yang, J."STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (Review)". International Journal of Oncology 41.4 (2012): 1181-1191.
Chicago
Wang, X., Crowe, P. J., Goldstein, D., Yang, J."STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (Review)". International Journal of Oncology 41, no. 4 (2012): 1181-1191. https://doi.org/10.3892/ijo.2012.1568