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Glioma Signaling pp 203–222Cite as

STAT Signaling in Glioma Cells

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1202))

Abstract

STAT (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that function as downstream effectors of cytokine and growth factor receptor signaling. The canonical JAK/STAT signaling pathway involves the activation of Janus kinases (JAK) or growth factors receptor kinases, phosphorylation of STAT proteins, their dimerization and translocation into the nucleus where STATs act as transcription factors with pleiotropic downstream effects. STAT signaling is tightly controlled with restricted kinetics due to action of its negative regulators. While STAT1 is believed to play an important role in growth arrest and apoptosis, and to act as a tumor suppressor, STAT3 and 5 are involved in promoting cell cycle progression, cellular transformation, and preventing apoptosis. Aberrant activation of STATs, in particular STAT3 and STAT5, have been found in a large number of human tumors, including gliomas and may contribute to oncogenesis. In this chapter, we have (1) summarized the mechanisms of STAT activation in normal and malignant signaling; (2) discussed evidence for the critical role of constitutively activated STAT3 and STAT5 in glioma pathobiology; (3) disclosed molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in gliomas.

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Abbreviations

Bcl-2:

B-cell lymphoma 2

Bcl-xL :

B-cell lymphoma-extra large

BRG1:

Brahma-related gene 1

EGFR:

Epidermal growth factor receptor

GAS:

IFNg-activated sequence

GBM:

Glioblastoma multiforme

GSC:

Glioma stem cells

IFNg :

Interferon g

IRF:

IFN regulatory factor

ISRE:

IFN-a/b–stimulated response element

JAK:

Janus kinase

Mcl-1:

Induced myeloid leukemia cell differentiation protein

MMP:

Metalloproteinase

ODN:

Oligodeoxynucleotide

PDGFR:

Platelet-derived growth factor receptor

PIAS:

Protein inhibitors of activated STAT

PTEN:

Phosphatase and tensin homolog

SH2:

Src homology domain 2

SOCS:

Suppressors of cytokine signaling

STAT:

Signal transducers and activators of transcription

TMZ:

Temozolomide

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

References

  • Adach-Kilon A, Swiatek-Machado K, Kaminska B, Dabrowski M (2011) Signal transducer and activator of transcription 1 (Stat1) maintains basal mRNA expression of pro-survival Stat3-target genes in glioma C6 cells. J Cell Biochem 112:3685–3694

    Article  PubMed  CAS  Google Scholar 

  • Akira S (2000) Roles of STAT3 defined by tissue-specific gene targeting. Oncogene 19:2607–2611

    Article  PubMed  CAS  Google Scholar 

  • Aziz MH, Hafeez BB, Sand JM, Pierce DB, Aziz SW, Dreckschmidt NE, Verma AK (2010) Protein kinase Cvarepsilon mediates Stat3Ser727 phosphorylation, Stat3-regulated gene expression, and cell invasion in various human cancer cell lines through integration with MAPK cascade (RAF-1, MEK1/2, and ERK1/2). Oncogene 29:3100–3109

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Baker BJ, Qin H, Benveniste EN (2008) Molecular basis of oncostatin M-induced SOCS-3 expression in astrocytes. Glia 56:1250–1262

    Article  PubMed  PubMed Central  Google Scholar 

  • Battle TE, Frank DA (2002) The role of STATs in apoptosis. Curr Mol Med 2:381–392

    Article  PubMed  CAS  Google Scholar 

  • Birner P, Toumangelova-Uzeir K, Natchev S, Guentchev M (2010) STAT3 tyrosine phosphorylation influences survival in glioblastoma. J Neurooncol 100:339–343

    Article  PubMed  CAS  Google Scholar 

  • Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, Greenberg ME (1997) Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278:477–483

    Article  PubMed  CAS  Google Scholar 

  • Borghouts C, Kunz C, Delis N, Groner B (2008) Monomeric recombinant peptide aptamers are required for efficient intracellular uptake and target inhibition. Mol Cancer Res 6:267–281

    Article  PubMed  CAS  Google Scholar 

  • Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, Irby R, Yeatman T, Courtneidge SA, Jove R (2001) Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci U S A 98:7319–7324

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brantley EC, Nabors LB, Gillespie GY, Choi YH, Palmer CA, Harrison K, Roarty K, Benveniste EN (2008) Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression. Clin Cancer Res 14:4694–4704

    Article  PubMed  CAS  Google Scholar 

  • Bromberg JF (2001) Activation of STAT proteins and growth control. Bioessays 23:161–169

    Article  PubMed  CAS  Google Scholar 

  • Bromberg J, Darnell JE Jr (2000) The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19:2468–2473

    Article  PubMed  CAS  Google Scholar 

  • Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell JE Jr (1998) Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol 18:2553–2558

    Article  PubMed  PubMed Central  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 

  • Broniscer A, Baker JN, Tagen M, Onar-Thomas A, Gilbertson RJ, Davidoff AM, Pai Panandiker AS, Leung W, Chin TK, Stewart CF, Kocak M, Rowland C, Merchant TE, Kaste SC, Gajjar A (2010) Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma. J Clin Oncol 28:4762–4768

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cao S, Wang C, Zheng Q, Qiao Y, Xu K, Jiang T, Wu A (2010) STAT5 regulates glioma cell invasion by pathways dependent and independent of STAT5 DNA binding. Neurosci Lett 487:228–233

    Article  PubMed  CAS  Google Scholar 

  • Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS, Jove R (1999) Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10:105–115

    Article  PubMed  CAS  Google Scholar 

  • Chen Z, Lund R, Aittokallio T, Kosonen M, Nevalainen O, Lahesmaa R (2003) Identification of novel IL-4/Stat6-regulated genes in T lymphocytes. J Immunol 171:3627–3635

    Article  PubMed  CAS  Google Scholar 

  • Chen F, Xu Y, Luo Y, Zheng D, Song Y, Yu K, Li H, Zhang L, Zhong W, Ji Y (2010) Down-regulation of Stat3 decreases invasion activity and induces apoptosis of human glioma cells. J Mol Neurosci 40:353–359

    Article  PubMed  CAS  Google Scholar 

  • Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K (1997) Specific inhibition of Stat3 signal transduction by PIAS3. Science 278:1803–1805

    Article  PubMed  CAS  Google Scholar 

  • Croker BA, Kiu H, Nicholson SE (2008) SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol 19:414–422

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Danial NN, Rothman P (2000) JAK-STAT signaling activated by Abl oncogenes. Oncogene 19:2523–2531

    Article  PubMed  CAS  Google Scholar 

  • Dasgupta A, Raychaudhuri B, Haqqi T, Prayson R, Van Meir EG, Vogelbaum M, Haque SJ (2009) Stat3 activation is required for the growth of U87 cell-derived tumours in mice. Eur J Cancer 45:677–684

    Article  PubMed  CAS  Google Scholar 

  • de la Iglesia N, Konopka G, Lim KL, Nutt CL, Bromberg JF, Frank DA, Mischel PS, Louis DN, Bonni A (2008a) Deregulation of a STAT3-interleukin 8 signaling pathway promotes human glioblastoma cell proliferation and invasiveness. J Neurosci 28:5870–5878

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • de la Iglesia N, Konopka G, Puram SV, Chan JA, Bachoo RM, You MJ, Levy DE, Depinho RA, Bonni A (2008b) Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev 22:449–462

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • de la Iglesia N, Puram SV, Bonni A (2009) STAT3 regulation of glioblastoma pathogenesis. Curr Mol Med 9:580–590

    Article  PubMed  PubMed Central  Google Scholar 

  • Decker T, Kovarik P (2000) Serine phosphorylation of STATs. Oncogene 19:2628–2637

    Article  PubMed  CAS  Google Scholar 

  • Ehret GB, Reichenbach P, Schindler U, Horvath CM, Fritz S, Nabholz M, Bucher P (2001) DNA binding specificity of different STAT proteins. Comparison of in vitro specificity with natural target sites. J Biol Chem 276:6675–6688

    Article  PubMed  CAS  Google Scholar 

  • Friedman HS, Bigner DD (2005) Glioblastoma multiforme and the epidermal growth factor receptor. N Engl J Med 353:1997–1999

    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, Caldas H, DeAngelis S, Li C, Li PK, Lin J (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  PubMed Central  CAS  Google Scholar 

  • Fujio Y, Kunisada K, Hirota H, Yamauchi-Takihara K, Kishimoto T (1997) Signals through gp130 upregulate bcl-x gene expression via STAT1-binding cis-element in cardiac myocytes. J Clin Invest 99:2898–2905

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fujita M, Zhu X, Sasaki K, Ueda R, Low KL, Pollack IF, Okada H (2008) Inhibition of STAT3 promotes the efficacy of adoptive transfer therapy using type-1 CTLs by modulation of the immunological microenvironment in a murine intracranial glioma. J Immunol 180:2089–2098

    Article  PubMed  CAS  Google Scholar 

  • Gabrusiewicz K, Ellert-Miklaszewska A, Lipko M, Sielska M, Frankowska M, Kaminska B (2011) Characteristics of the alternative phenotype of microglia/macrophages and its modulation in experimental gliomas. PLoS One 6:e23902

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021

    Article  PubMed  CAS  Google Scholar 

  • Gao L, Li F, Dong B, Zhang J, Rao Y, Cong Y, Mao B, Chen X (2010) Inhibition of STAT3 and ErbB2 suppresses tumor growth, enhances radiosensitivity, and induces mitochondria-dependent apoptosis in glioma cells. Int J Radiat Oncol Biol Phys 77:1223–1231

    Article  PubMed  CAS  Google Scholar 

  • Gesbert F, Griffin JD (2000) Bcr/Abl activates transcription of the Bcl-X gene through STAT5. Blood 96:2269–2276

    Article  PubMed  CAS  Google Scholar 

  • Greenhalgh CJ, Hilton DJ (2001) Negative regulation of cytokine signaling. J Leukoc Biol 70:348–356

    PubMed  CAS  Google Scholar 

  • Gu F, Hata R, Ma YJ, Tanaka J, Mitsuda N, Kumon Y, Hanakawa Y, Hashimoto K, Nakajima K, Sakanaka M (2005) Suppression of Stat3 promotes neurogenesis in cultured neural stem cells. J Neurosci Res 81:163–171

    Article  PubMed  CAS  Google Scholar 

  • Gu J, Li G, Sun T, Su Y, Zhang X, Shen J, Tian Z, Zhang J (2008) Blockage of the STAT3 signaling pathway with a decoy oligonucleotide suppresses growth of human malignant glioma cells. J Neurooncol 89:9–17

    Article  PubMed  CAS  Google Scholar 

  • Hartman SE, Bertone P, Nath AK, Royce TE, Gerstein M, Weissman S, Snyder M (2005) Global changes in STAT target selection and transcription regulation upon interferon treatments. Genes Dev 19:2953–2968

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Haspel RL, Darnell JE Jr (1999) A nuclear protein tyrosine phosphatase is required for the inactivation of Stat1. Proc Natl Acad Sci U S A 96:10188–10193

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hatiboglu MA, Wei J, Wu AS, Heimberger AB (2010) Immune therapeutic targeting of glioma cancer stem cells. Target Oncol 5:217–227

    Article  PubMed  PubMed Central  Google Scholar 

  • Haybaeck J, Obrist P, Schindler CU, Spizzo G, Doppler W (2007) STAT-1 expression in human glioblastoma and peritumoral tissue. Anticancer Res 27:3829–3835

    PubMed  CAS  Google Scholar 

  • He B, You L, Uematsu K, Zang K, Xu Z, Lee AY, Costello JF, McCormick F, Jablons DM (2003) SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci U S A 100:14133–14138

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Heim MH, Kerr IM, Stark GR, Darnell JE Jr (1995) Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway. Science 267:1347–1349

    Article  PubMed  CAS  Google Scholar 

  • Heimberger AB, Priebe W (2008) Small molecular inhibitors of p-STAT3: novel agents for treatment of primary and metastatic CNS cancers. Recent Pat CNS Drug Discov 3:179–188

    Article  PubMed  CAS  Google Scholar 

  • Hoey T, Zhang S, Schmidt N, Yu Q, Ramchandani S, Xu X, Naeger LK, Sun YL, Kaplan MH (2003) Distinct requirements for the naturally occurring splice forms Stat4alpha and Stat4beta in IL-12 responses. EMBO J 22:4237–4248

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Horvath CM, Wen Z, Darnell JE Jr (1995) A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. Genes Dev 9:984–994

    Article  PubMed  CAS  Google Scholar 

  • Hussain SF, Kong LY, Jordan J, Conrad C, Madden T, Fokt I, Priebe W, Heimberger AB (2007) A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res 67:9630–9636

    Article  PubMed  CAS  Google Scholar 

  • Ivashkiv LB, Hu X (2004) Signaling by STATs. Arthritis Res Ther 6:159–168

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Iwamaru A, Szymanski S, Iwado E, Aoki H, Yokoyama T, Fokt I, Hess K, Conrad C, Madden T, Sawaya R, Kondo S, Priebe W, Kondo Y (2007) A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene 26:2435–2444

    Article  PubMed  CAS  Google Scholar 

  • Jatiani SS, Cosenza SC, Reddy MV, Ha JH, Baker SJ, Samanta AK, Olnes MJ, Pfannes L, Sloand EM, Arlinghaus RB, Reddy EP (2010) A non-ATP-competitive dual inhibitor of JAK2 and BCR-ABL kinases: elucidation of a novel therapeutic spectrum based on substrate competitive inhibition. Genes Cancer 1:331–345

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • John S, Vinkemeier U, Soldaini E, Darnell JE Jr, Leonard WJ (1999) The significance of tetramerization in promoter recruitment by Stat5. Mol Cell Biol 19:1910–1918

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Khan KD, Shuai K, Lindwall G, Maher SE, Darnell JE Jr, Bothwell AL (1993) Induction of the Ly-6A/E gene by interferon alpha/beta and gamma requires a DNA element to which a tyrosine-phosphorylated 91-kDa protein binds. Proc Natl Acad Sci U S A 90:6806–6810

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285:1–24

    Article  PubMed  CAS  Google Scholar 

  • Konnikova L, Kotecki M, Kruger MM, Cochran BH (2003) Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer 3:23

    Article  PubMed  PubMed Central  Google Scholar 

  • Korpelainen EI, Karkkainen M, Gunji Y, Vikkula M, Alitalo K (1999) Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. Oncogene 18:1–8

    Article  PubMed  CAS  Google Scholar 

  • Kostianovsky AM, Maier LM, Anderson RC, Bruce JN, Anderson DE (2008) Astrocytic regulation of human monocytic/microglial activation. J Immunol 181:5425–5432

    Article  PubMed  CAS  Google Scholar 

  • Kubo M, Ransom J, Webb D, Hashimoto Y, Tada T, Nakayama T (1997) T-cell subset-specific expression of the IL-4 gene is regulated by a silencer element and STAT6. EMBO J 16:4007–4020

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lehmann U, Schmitz J, Weissenbach M, Sobota RM, Hortner M, Friederichs K, Behrmann I, Tsiaris W, Sasaki A, Schneider-Mergener J, Yoshimura A, Neel BG, Heinrich PC, Schaper F (2003) SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. J Biol Chem 278:661–671

    Article  PubMed  CAS  Google Scholar 

  • Leong PL, Andrews GA, Johnson DE, Dyer KF, Xi S, Mai JC, Robbins PD, Gadiparthi S, Burke NA, Watkins SF, Grandis JR (2003) Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc Natl Acad Sci U S A 100:4138–4143

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Letimier FA, Passini N, Gasparian S, Bianchi E, Rogge L (2007) Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rbeta2 expression during human Th1 cell differentiation. EMBO J 26:1292–1302

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li GH, Wei H, Lv SQ, Ji H, Wang DL (2010) Knockdown of STAT3 expression by RNAi suppresses growth and induces apoptosis and differentiation in glioblastoma stem cells. Int J Oncol 37:103–110

    PubMed  Google Scholar 

  • Liang QC, Xiong H, Zhao ZW, Jia D, Li WX, Qin HZ, Deng JP, Gao L, Zhang H, Gao GD (2009) Inhibition of transcription factor STAT5b suppresses proliferation, induces G1 cell cycle arrest and reduces tumor cell invasion in human glioblastoma multiforme cells. Cancer Lett 273:164–171

    Article  PubMed  CAS  Google Scholar 

  • Lin L, Hutzen B, Li PK, Ball S, Zuo M, DeAngelis S, Foust E, Sobo M, Friedman L, Bhasin D, Cen L, Li C, Lin J (2010) A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells. Neoplasia 12:39–50

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K (1998) Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci U S A 95:10626–10631

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lo RK, Cheung H, Wong YH (2003) Constitutively active Galpha16 stimulates STAT3 via a c-Src/JAK- and ERK-dependent mechanism. J Biol Chem 278:52154–52165

    Article  PubMed  CAS  Google Scholar 

  • Lo HW, Cao X, Zhu H, Ali-Osman F (2008) Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators. Clin Cancer Res 14:6042–6054

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Look DC, Pelletier MR, Tidwell RM, Roswit WT, Holtzman MJ (1995) Stat1 depends on transcriptional synergy with Sp1. J Biol Chem 270:30264–30267

    Article  PubMed  CAS  Google Scholar 

  • Lord JD, McIntosh BC, Greenberg PD, Nelson BH (2000) The IL-2 receptor promotes lymphocyte proliferation and induction of the c-myc, bcl-2, and bcl-x genes through the trans-activation domain of Stat5. J Immunol 164:2533–2541

    Article  PubMed  CAS  Google Scholar 

  • Lund RJ, Chen Z, Scheinin J, Lahesmaa R (2004) Early target genes of IL-12 and STAT4 signaling in th cells. J Immunol 172:6775–6782

    Article  PubMed  CAS  Google Scholar 

  • Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafontaine P, Bernstein KE (1995) Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 375:247–250

    Article  PubMed  CAS  Google Scholar 

  • Martini M, Pallini R, Luongo G, Cenci T, Lucantoni C, Larocca LM (2008) Prognostic relevance of SOCS3 hypermethylation in patients with glioblastoma multiforme. Int J Cancer 123:2955–2960

    Article  PubMed  CAS  Google Scholar 

  • Mizoguchi M, Betensky RA, Batchelor TT, Bernay DC, Louis DN, Nutt CL (2006) Activation of STAT3, MAPK, and AKT in malignant astrocytic gliomas: correlation with EGFR status, tumor grade, and survival. J Neuropathol Exp Neurol 65:1181–1188

    Article  PubMed  CAS  Google Scholar 

  • Nagel-Wolfrum K, Buerger C, Wittig I, Butz K, Hoppe-Seyler F, Groner B (2004) 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 2:170–182

    PubMed  CAS  Google Scholar 

  • Naik SM, Shibagaki N, Li LJ, Quinlan KL, Paxton LL, Caughman SW (1997) Interferon gamma-dependent induction of human intercellular adhesion molecule-1 gene expression involves activation of a distinct STAT protein complex. J Biol Chem 272:1283–1290

    Article  PubMed  CAS  Google Scholar 

  • Ni Z, Bremner R (2007) Brahma-related gene 1-dependent STAT3 recruitment at IL-6-inducible genes. J Immunol 178:345–351

    Article  PubMed  CAS  Google Scholar 

  • Nicholson SE, De Souza D, Fabri LJ, Corbin J, Willson TA, Zhang JG, Silva A, Asimakis M, Farley A, Nash AD, Metcalf D, Hilton DJ, Nicola NA, Baca M (2000) Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci U S A 97:6493–6498

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, Huang HJ (1994) A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci U S A 91:7727–7731

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Niwa H, Burdon T, Chambers I, Smith A (1998) Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev 12:2048–2060

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • O’Shea JJ, Gadina M, Schreiber RD (2002) Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 109(Suppl):S121–S131

    Article  PubMed  Google Scholar 

  • O’Sullivan A, Chang HC, Yu Q, Kaplan MH (2004) STAT4 is required for interleukin-12-induced chromatin remodeling of the CD25 locus. J Biol Chem 279:7339–7345

    Article  PubMed  CAS  Google Scholar 

  • Ouchi T, Lee SW, Ouchi M, Aaronson SA, Horvath CM (2000) Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-gamma target genes. Proc Natl Acad Sci U S A 97:5208–5213

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pesu M, Muul L, Kanno Y, O’Shea JJ (2006) Proprotein convertase furin is preferentially expressed in T helper 1 cells and regulates interferon gamma. Blood 108:983–985

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Premkumar DR, Jane EP, Agostino NR, Scialabba JL, Pollack IF (2010) Dasatinib synergizes with JSI-124 to inhibit growth and migration and induce apoptosis of malignant human glioma cells. J Carcinog 9:7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rahaman SO, Harbor PC, Chernova O, Barnett GH, Vogelbaum MA, Haque SJ (2002) Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene 21:8404–8413

    Article  PubMed  CAS  Google Scholar 

  • Rajan P, McKay RD (1998) Multiple routes to astrocytic differentiation in the CNS. J Neurosci 18:3620–3629

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ramana CV, Chatterjee-Kishore M, Nguyen H, Stark GR (2000) Complex roles of Stat1 in regulating gene expression. Oncogene 19:2619–2627

    Article  PubMed  CAS  Google Scholar 

  • Raz R, Lee CK, Cannizzaro LA, D’Eustachio P, Levy DE (1999) Essential role of STAT3 for embryonic stem cell pluripotency. Proc Natl Acad Sci U S A 96:2846–2851

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reddy EP, Korapati A, Chaturvedi P, Rane S (2000) IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled. Oncogene 19:2532–2547

    Article  PubMed  CAS  Google Scholar 

  • Schaefer LK, Ren Z, Fuller GN, Schaefer TS (2002) Constitutive activation of Stat3alpha in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2). Oncogene 21:2058–2065

    Article  PubMed  CAS  Google Scholar 

  • Schiavone D, Avalle L, Dewilde S, Poli V (2011) The immediate early genes Fos and Egr1 become STAT1 transcriptional targets in the absence of STAT3. FEBS Lett 585:2455–2460

    Article  PubMed  CAS  Google Scholar 

  • Schmidt D, Muller S (2003) PIAS/SUMO: new partners in transcriptional regulation. Cell Mol Life Sci 60:2561–2574

    Article  PubMed  CAS  Google Scholar 

  • Senft C, Priester M, Polacin M, Schroder K, Seifert V, Kogel D, Weissenberger J (2010) Inhibition of the JAK-2/STAT3 signaling pathway impedes the migratory and invasive potential of human glioblastoma cells. J Neurooncol 101:393–403

    Article  PubMed  CAS  Google Scholar 

  • Shen J, Li R, Li G (2009) Inhibitory effects of decoy-ODN targeting activated STAT3 on human glioma growth in vivo. In Vivo 23:237–243

    PubMed  CAS  Google Scholar 

  • Sherry MM, Reeves A, Wu JK, Cochran BH (2009) STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 27:2383–2392

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shuai K, Liu B (2005) Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 5:593–605

    Article  PubMed  CAS  Google Scholar 

  • Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

    PubMed  CAS  Google Scholar 

  • Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401

    Article  PubMed  CAS  Google Scholar 

  • Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF (1999) Fetal anemia and apoptosis of red cell progenitors in Stat5a−/−5b−/− mice: a direct role for Stat5 in Bcl-X(L) induction. Cell 98:181–191

    Article  PubMed  CAS  Google Scholar 

  • Stea B, Falsey R, Kislin K, Patel J, Glanzberg H, Carey S, Ambrad AA, Meuillet EJ, Martinez JD (2003) Time and dose-dependent radiosensitization of the glioblastoma multiforme U251 cells by the EGF receptor tyrosine kinase inhibitor ZD1839 (‘Iressa’). Cancer Lett 202:43–51

    Article  PubMed  CAS  Google Scholar 

  • Stephanou A, Latchman DS (2005) Opposing actions of STAT-1 and STAT-3. Growth Factors 23:177–182

    Article  PubMed  CAS  Google Scholar 

  • Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  Google Scholar 

  • Su Y, Li G, Zhang X, Gu J, Zhang C, Tian Z, Zhang J (2008) JSI-124 inhibits glioblastoma multiforme cell proliferation through G(2)/M cell cycle arrest and apoptosis augment. Cancer Biol Ther 7:1243–1249

    Article  PubMed  CAS  Google Scholar 

  • Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, Akira S (1998) Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol 161:4652–4660

    PubMed  CAS  Google Scholar 

  • Thieu VT, Yu Q, Chang HC, Yeh N, Nguyen ET, Sehra S, Kaplan MH (2008) Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination. Immunity 29:679–690

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Turkson J (2004) STAT proteins as novel targets for cancer drug discovery. Expert Opin Ther Targets 8:409–422

    Article  PubMed  CAS  Google Scholar 

  • Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot RP, Jove R (1998) Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol Cell Biol 18:2545–2552

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Turkson J, Bowman T, Adnane J, Zhang Y, Djeu JY, Sekharam M, Frank DA, Holzman LB, Wu J, Sebti S, Jove R (1999) 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 19:7519–7528

    Article  PubMed  PubMed Central  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 

  • Valente AJ, Xie JF, Abramova MA, Wenzel UO, Abboud HE, Graves DT (1998) A complex element regulates IFN-gamma-stimulated monocyte chemoattractant protein-1 gene transcription. J Immunol 161:3719–3728

    PubMed  CAS  Google Scholar 

  • Vescovi AL, Galli R, Reynolds BA (2006) Brain tumour stem cells. Nat Rev Cancer 6:425–436

    Article  PubMed  CAS  Google Scholar 

  • Vila-Coro AJ, Rodriguez-Frade JM, Martin De Ana A, Moreno-Ortiz MC, Martinez AC, Mellado M (1999) The chemokine SDF-1alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. FASEB J 13:1699–1710

    Article  PubMed  CAS  Google Scholar 

  • Villalva C, Martin-Lanneree S, Cortes U, Dkhissi F, Wager M, Le Corf A, Tourani JM, Dusanter-Fourt I, Turhan AG, Karayan-Tapon L (2010) STAT3 is essential for the maintenance of neurosphere-initiating tumor cells in patients with glioblastomas: a potential for targeted therapy? Int J Cancer 128:826–838

    Article  CAS  Google Scholar 

  • Wagner BJ, Hayes TE, Hoban CJ, Cochran BH (1990) The SIF binding element confers sis/PDGF inducibility onto the c-fos promoter. EMBO J 9:4477–4484

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang H, Zhang W, Huang HJ, Liao WS, Fuller GN (2004) Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas. Lab Invest 84:941–951

    Article  PubMed  CAS  Google Scholar 

  • Wang H, Lathia JD, Wu Q, Wang J, Li Z, Heddleston JM, Eyler CE, Elderbroom J, Gallagher J, Schuschu J, MacSwords J, Cao Y, McLendon RE, Wang XF, Hjelmeland AB, Rich JN (2009) Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth. Stem Cells 27:2393–2404

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wei J, Barr J, Kong LY, Wang Y, Wu A, Sharma AK, Gumin J, Henry V, Colman H, Sawaya R, Lang FF, Heimberger AB (2010) Glioma-associated cancer-initiating cells induce immunosuppression. Clin Cancer Res 16:461–473

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Weissenberger J, Loeffler S, Kappeler A, Kopf M, Lukes A, Afanasieva TA, Aguzzi A, Weis J (2004) IL-6 is required for glioma development in a mouse model. Oncogene 23:3308–3316

    Article  PubMed  CAS  Google Scholar 

  • Weissenberger J, Priester M, Bernreuther C, Rakel S, Glatzel M, Seifert V, Kogel D (2010) Dietary curcumin attenuates glioma growth in a syngeneic mouse model by inhibition of the JAK1,2/STAT3 signaling pathway. Clin Cancer Res 16:5781–5795

    Article  PubMed  CAS  Google Scholar 

  • Wen Z, Zhong Z, Darnell JE Jr (1995) Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82:241–250

    Article  PubMed  CAS  Google Scholar 

  • Wirnsberger G, Hebenstreit D, Posselt G, Horejs-Hoeck J, Duschl A (2006) IL-4 induces expression of TARC/CCL17 via two STAT6 binding sites. Eur J Immunol 36:1882–1891

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wong M, Fish EN (1998) RANTES and MIP-1alpha activate stats in T cells. J Biol Chem 273:309–314

    Article  PubMed  CAS  Google Scholar 

  • Wormald S, Hilton DJ, Smyth GK, Speed TP (2006) Proximal genomic localization of STAT1 binding and regulated transcriptional activity. BMC Genomics 7:254

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yang F, Brown C, Buettner R, Hedvat M, Starr R, Scuto A, Schroeder A, Jensen M, Jove R (2010) Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3. Mol Cancer Ther 9:953–962

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yiin JJ, Hu B, Schornack PA, Sengar RS, Liu KW, Feng H, Lieberman FS, Chiou SH, Sarkaria JN, Wiener EC, Ma HI, Cheng SY (2010) ZD6474, a multitargeted inhibitor for receptor tyrosine kinases, suppresses growth of gliomas expressing an epidermal growth factor receptor mutant, EGFRvIII, in the brain. Mol Cancer Ther 9:929–941

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yoshimura A (2005) Negative regulation of cytokine signaling. Clin Rev Allergy Immunol 28:205–220

    Article  PubMed  CAS  Google Scholar 

  • Yu H, Jove R (2004) The STATs of cancer–new molecular targets come of age. Nat Rev Cancer 4:97–105

    Article  PubMed  CAS  Google Scholar 

  • Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, Jove R (1995) Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269:81–83

    Article  PubMed  CAS  Google Scholar 

  • Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7:41–51

    Article  PubMed  CAS  Google Scholar 

  • Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yuan X, Curtin J, Xiong Y, Liu G, Waschsmann-Hogiu S, Farkas DL, Black KL, Yu JS (2004) Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23:9392–9400

    Article  PubMed  CAS  Google Scholar 

  • Yue P, Turkson J (2009) Targeting STAT3 in cancer: how successful are we? Expert Opin Investig Drugs 18:45–56

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang F, Li C, Halfter H, Liu J (2003) Delineating an oncostatin M-activated STAT3 signaling pathway that coordinates the expression of genes involved in cell cycle regulation and extracellular matrix deposition of MCF-7 cells. Oncogene 22:894–905

    Article  CAS  Google Scholar 

  • Zhang Y, Cheng MB, Zhang YJ, Zhong X, Dai H, Yan L, Wu NH, Shen YF (2010) A switch from hBrm to Brg1 at IFNgamma-activated sequences mediates the activation of human genes. Cell Res 20:1345–1360

    Article  PubMed  CAS  Google Scholar 

  • Zhou H, Miki R, Eeva M, Fike FM, Seligson D, Yang L, Yoshimura A, Teitell MA, Jamieson CA, Cacalano NA (2007) Reciprocal regulation of SOCS 1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme. Clin Cancer Res 13:2344–2353

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Kavita Ramji for a critical reading of the manuscript. Studies were supported by a grant N N405621938 from the Ministry of Science and Higher Education.

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  1. Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St, PL 02-093, Warsaw, Poland

    Karolina Swiatek-Machado & Bozena Kaminska

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  1. Karolina Swiatek-Machado
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  2. Bozena Kaminska
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Correspondence to Karolina Swiatek-Machado .

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  1. Biochemistry, Nencki Institute of Experimental Biology, Warsaw, Poland

    Jolanta Barańska

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Swiatek-Machado, K., Kaminska, B. (2020). STAT Signaling in Glioma Cells. In: Barańska, J. (eds) Glioma Signaling. Advances in Experimental Medicine and Biology, vol 1202. Springer, Cham. https://doi.org/10.1007/978-3-030-30651-9_10

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