Skip to main content
SpringerLink
Log in

STAT Signaling in the Pathogenesis and Treatment of Cancer

  • Chapter
  • First Online:
Signaling Pathways in Cancer Pathogenesis and Therapy

Abstract

The malignant behavior of a cancer cell is driven largely by the pattern of gene expression within that cell. Cancer cells are often characterized by the inappropriate activation of transcription factors that regulate genes controlling key cellular processes such as cell cycle progression, survival, and self-renewal. One family of transcription factors that play a central role in regulating these processes under physiological conditions is STATs. The seven STAT family members are physiologically activated by tyrosine phosphorylation, which is induced by a range of cytokines and growth factors. The phosphorylation of STATs is normally rapid and transient to ensure that their target genes are expressed in a controlled manner. In a wide range of human cancers, STATs, particularly STAT3 and STAT5, are activated constitutively. This leads to increased expression of target genes, which drives the malignant behavior of these cells. Understanding how STATs become activated provides insights into key aspects of tumor pathogenesis. In addition, given the central role that STATs play in tumor biology, STATs have emerged as attractive targets for cancer therapy. Several approaches, including rational design and cell-based chemical library screens, have yielded a number of potentially important STAT inhibitors that are now being introduced into clinical trials. Translational research in the area of STAT signaling is likely to continue to provide insight into both the molecular pathogenesis of cancer as well as novel therapeutic strategies for treating this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Alvarez JV, Febbo PG, Ramaswamy S, Loda M, Richardson A, Frank DA (2005) Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors. Cancer Res 65:5054–5062

    Article  PubMed  CAS  Google Scholar 

  • Boehm AL, Sen M, Seethala R, Gooding WE, Freilino M, Wong SM, Wang S, Johnson DE, Grandis JR (2008) Combined targeting of epidermal growth factor receptor, signal transducer and activator of transcription-3, and Bcl-X(L) enhances antitumor effects in squamous cell carcinoma of the head and neck. Mol Pharmacol 73:1632–1642

    Article  PubMed  CAS  Google Scholar 

  • Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE Jr (1999) Stat3 as an oncogene. Cell 98:295–303

    Article  PubMed  CAS  Google Scholar 

  • Bruns HA, Kaplan MH (2006) The role of constitutively active Stat6 in leukemia and lymphoma. Crit Rev Oncol Hematol 57:245–253

    Article  PubMed  Google Scholar 

  • Chan KS, Sano S, Kiguchi K, Anders J, Komazawa N, Takeda J, DiGiovanni J (2004) Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J Clin Invest 114:720–728

    PubMed  CAS  Google Scholar 

  • Chen CL, Loy A, Cen L, Chan C, Hsieh FC, Cheng G, Wu B, Qualman SJ, Kunisada K, Yamauchi-Takihara K, Lin J (2007) Signal transducer and activator of transcription 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells. BMC Cancer 7:111

    Article  PubMed  Google Scholar 

  • Chen CL, Cen L, Kohout J, Hutzen B, Chan C, Hsieh FC, Loy A, Huang V, Cheng G, Lin J (2008) Signal transducer and activator of transcription 3 activation is associated with bladder cancer cell growth and survival. Mol Cancer 7:78

    Article  PubMed  Google Scholar 

  • Chim CS, Fung TK, Cheung WC, Liang R, Kwong YL (2004) SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood 103:4630–4635

    Article  PubMed  CAS  Google Scholar 

  • Chung J, Uchida E, Grammer TC, Blenis J (1997) STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol 17:6508–6516

    PubMed  CAS  Google Scholar 

  • Fletcher S, Drewry JA, Shahani VM, Page BD, Gunning PT (2009) Molecular disruption of oncogenic signal transducer and activator of transcription 3 (STAT3) protein. Biochem Cell Biol 87:825–833

    Article  PubMed  CAS  Google Scholar 

  • Frank DA (2006) STAT inhibition in the treatment of cancer: transcription factors as targets for molecular therapy. Curr Cancer Therapy Reviews 2:57–65

    Article  CAS  Google Scholar 

  • Frank DA (2007) STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett 251:199–210

    Article  PubMed  CAS  Google Scholar 

  • Frank DA, Mahajan S, Ritz J (1997) B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. J Clin Invest 100:3140–3148

    Article  PubMed  CAS  Google Scholar 

  • Fuh B, Sobo M, Cen L, Josiah D, Hutzen B, Cisek K, Bhasin D, Regan N, Lin L, Chan C et al (2009) LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model. Br J Cancer 100:106–112

    Article  PubMed  CAS  Google Scholar 

  • Galm O, Yoshikawa H, Esteller M, Osieka R, Herman JG (2003) SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Blood 101:2784–2788

    Article  PubMed  CAS  Google Scholar 

  • Germain D, Frank DA (2007) Targeting the cytoplasmic and nuclear functions of STAT3 for cancer therapy. Clin Cancer Res 13:5665–5669

    Article  PubMed  CAS  Google Scholar 

  • Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE (2009) Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 324:1713–1716

    Article  PubMed  CAS  Google Scholar 

  • Guiter C, Dusanter-Fourt I, Copie-Bergman C, Boulland M-L, le Gouvello S, Gaulard P, Leroy K, Castellano F (2004) Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma. Blood 104:543–549

    Article  PubMed  CAS  Google Scholar 

  • Hazan-Halevy I, Harris D, Liu Z, Liu J, Li P, Chen X, Shanker S, Ferrajoli A, Keating MJ, Estrov Z (2010) STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood 115:2852–2863

    Article  PubMed  CAS  Google Scholar 

  • Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML et al (2007) STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 357:1608–1619

    Article  PubMed  CAS  Google Scholar 

  • Jackson PK (2001) A new RING for SUMO: wrestling transcription responses into nuclear bodies with PIAS family E3 SUMO ligases. Genes Dev 15:3053–3058

    Article  PubMed  CAS  Google Scholar 

  • Jain N, Zhang T, Fong SL, Lim CP, Cao X (1998) Repression of Stat3 activity by activation of mitogen-activated protein kinase (MAPK). Oncogene 17:3157–3167

    Article  PubMed  CAS  Google Scholar 

  • Jing N, Li Y, Xiong W, Sha W, Jing L, Tweardy DJ (2004) G-quartet oligonucleotides: a new class of signal transducer and activator of transcription 3 inhibitors that suppress growth of prostate and breast tumors through induction of apoptosis. Cancer Res 64:6603–6609

    Article  PubMed  CAS  Google Scholar 

  • Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, Kishimoto T (1988) Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332:83–85

    Article  PubMed  CAS  Google Scholar 

  • Leeman RJ, Lui VW, Grandis JR (2006) STAT3 as a therapeutic target in head and neck cancer. Expert Opin Biol Ther 6:231–241

    Article  PubMed  CAS  Google Scholar 

  • Levy DE, Gilliland DG (2000) Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice. Oncogene 19:2505–2510

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Robinson GW, Wagner K-U, Garrett L, Wynshaw-Boris A, Hennighausen L (1997) Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev 11:179–186

    Article  PubMed  CAS  Google Scholar 

  • Lui VW, Boehm AL, Koppikar P, Leeman RJ, Johnson D, Ogagan M, Childs E, Freilino M, Grandis JR (2007) Antiproliferative mechanisms of a transcription factor decoy targeting signal transducer and activator of transcription (STAT) 3: the role of STAT1. Mol Pharmacol 71:1435–1443

    Article  PubMed  CAS  Google Scholar 

  • Lynch RA, Etchin J, Battle TE, Frank DA (2007) A small-molecule enhancer of signal transducer and activator of transcription 1 transcriptional activity accentuates the antiproliferative effects of IFN-gamma in human cancer cells. Cancer Res 67:1254–1261

    Article  PubMed  CAS  Google Scholar 

  • Marotta LLC, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, Bloushtain-Qimron N, Kim JJ, Choudhury SA, Maruyama R et al (2011) The JAK2/STAT3 signaling pathway is required for growth of CD44  +  CD24– stem cell–like breast cancer cells in human tumors. J Clin Invest

    Google Scholar 

  • Nelson EA, Walker SR, Kepich A, Gashin LB, Hideshima T, Ikeda H, Chauhan D, Anderson KC, Frank DA (2008) Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood 112:5095–5102

    Article  PubMed  CAS  Google Scholar 

  • Nelson EA, Sharma SV, Settleman J, Frank DA (2011a) A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation. Oncotargets 2(6):518–524

    Google Scholar 

  • Nelson EA, Walker SR, Weisberg E, Bar-Natan M, Barrett R, Gashin LB, Terrell S, Klitgaard JL, Santo L, Addorio MR et al (2011b) The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood 117:3421–3429

    Article  PubMed  CAS  Google Scholar 

  • Schwaller J, Parganas E, Wang D, Cain D, Aster JC, Williams IR, Lee C-K, Gerthner R, Kitamura T, Frantsve J et al (2000) Stat5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2. Mol Cell 6:693–704

    Article  PubMed  CAS  Google Scholar 

  • Sen M, Tosca PJ, Zwayer C, Ryan MJ, Johnson JD, Knostman KA, Giclas PC, Peggins JO, Tomaszewski JE, McMurray TP, Li C, Leibowitz MS, Ferris RL, Gooding WE, Thomas SM, Johnson DE, Grandis JR (2009) Lack of toxicity of a STAT3 decoy oligonucleotide. Cancer Chemother Pharmacol 63:983–995

    Article  PubMed  CAS  Google Scholar 

  • Socolovsky M, Nam H, Fleming MD, Haase VH, Brugnara C, Lodish HF (2001) Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. Blood 98:3261–3273

    Article  PubMed  CAS  Google Scholar 

  • Song H, Wang R, Wang S, Lin J (2005) 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

    Article  PubMed  CAS  Google Scholar 

  • Szczepek AJ, Belch AR, Pilarski LM (2001) Expression of IL-6 and IL-6 receptors by circulating clonotypic B cells in multiple myeloma: potential for autocrine and paracrine networks. Exp Hematol 29:1076–1081

    Article  PubMed  CAS  Google Scholar 

  • Trauger JW, Baird EE, Dervan PB (1996) Recognition of DNA by designed ligands at subnanomolar concentrations. Nature 382:559–561

    Article  PubMed  CAS  Google Scholar 

  • Turkson J, Ryan D, Kim JS, Zhang Y, Chen Z, Haura E, Laudano A, Sebti S, Hamilton AD, Jove R (2001) Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. J Biol Chem 276:45443–45455

    Article  PubMed  CAS  Google Scholar 

  • Turkson J, Kim JS, Zhang S, Yuan J, Huang M, Glenn M, Haura E, Sebti S, Hamilton AD, Jove R (2004) Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol Cancer Ther 3:261–269

    PubMed  CAS  Google Scholar 

  • Uchiyama H, Barut BA, Mohrbacher AF, Chauhan D, Anderson KC (1993) Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood 82:3712–3720

    PubMed  CAS  Google Scholar 

  • Walker SR, Nelson EA, Frank DA (2007) STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas. Oncogene 26:224–233

    Article  PubMed  CAS  Google Scholar 

  • Walker SR, Nelson EA, Zou L, Chaudhury M, Signoretti S, Richardson A, Frank DA (2009) Reciprocal effects of STAT5 and STAT3 in breast cancer. Mol Cancer Res 7:966–976

    Article  PubMed  CAS  Google Scholar 

  • Walker SR, Chaudhury M, Nelson EA, Frank DA (2010) Microtubule-targeted chemotherapeutic agents inhibit STAT3 signaling. Mol Pharmacology 78(5):903–908

    Article  CAS  Google Scholar 

  • Wang LH, Yang XY, Kirken RA, Resau JH, Farrar WL (2000) Targeted disruption of Stat6 DNA binding activity by an oligonucleotide decoy blocks IL-4-driven TH2 cell response. Blood 95:1249–1257

    PubMed  CAS  Google Scholar 

  • Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D et al (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10:48–54

    Article  PubMed  Google Scholar 

  • Xi S, Gooding WE, Grandis JR (2005) In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy. Oncogene 24:970–979

    Article  PubMed  CAS  Google Scholar 

  • Yang J, Stark GR (2008) Roles of unphosphorylated STATs in signaling. Cell Res 18:443–451

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA

    Sarah R. Walker & David A. Frank

Authors
  1. Sarah R. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David A. Frank
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David A. Frank .

Editor information

Editors and Affiliations

  1. Dana-Farber Cancer Institute, Dept. Medical Oncology, Harvard Medical School, Binney St. 44, Boston, 02115, Massachusetts, USA

    David A. Frank

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Walker, S.R., Frank, D.A. (2012). STAT Signaling in the Pathogenesis and Treatment of Cancer. In: Frank, D. (eds) Signaling Pathways in Cancer Pathogenesis and Therapy. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1216-8_7

Download citation

Publish with us

Policies and ethics

Search

Navigation