Skip to main content

Advertisement

SpringerLink
Log in

STAT3 in medulloblastoma: a key transcriptional regulator and potential therapeutic target

  • Review
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Medulloblastoma is the most common malignant brain tumor of childhood accounting for about 60% of all pediatric embryonal tumors. Despite improvements in the overall survival rate, this tumor still lacks an efficient, reliable, and less toxic therapeutic approach. Characterization of the molecular mechanisms involved in medulloblastoma initiation and progression is a crucial step for the development of effective therapies. Signal transducer and activator of transcription 3 is a convergence point for several signaling cascades that are implicated in medulloblastoma tumorigenesis. Accumulated evidence has revealed the pivotal role of signal transducer and activator of transcription 3 in medulloblastoma pathogenesis such as proliferation, survival, angiogenesis, and immunosuppression as well as maintenance, drug resistance, and recurrence. In this review, we focus on the role of signal transducer and activator of transcription 3 in medulloblastoma tumorigenesis and discuss the recent advances of signal transducer and activator of transcription 3 inhibition as a promising developed strategy for medulloblastoma therapy.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

References

  1. Khatua S et al (2018) Childhood medulloblastoma: current therapies, emerging molecular landscape and newer therapeutic insights. Curr Neuropharmacol 16(7):1045–1058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Audi ZF et al (2021) Immunosuppression in medulloblastoma: insights into cancer immunity and immunotherapy. Curr Treat Options Oncol 22(9):83

    Article  PubMed  Google Scholar 

  3. Ostrom QT et al (2018) CBTRUS statistical report primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Neuro Oncol 20(suppl_4):vi1-iv86

    Article  Google Scholar 

  4. Komori T (2017) The 2016 WHO classification of tumours of the central nervous System: the major points of revision. Neurol Med Chir (Tokyo) 57(7):301–311

    Article  Google Scholar 

  5. Northcott PA et al (2012) Medulloblastomics: the end of the beginning. Nat Rev Cancer 12(12):818–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kaur K et al (2016) Integrating molecular subclassification of medulloblastomas into routine clinical practice: a simplified approach. Brain Pathol 26(3):334–343

    Article  CAS  PubMed  Google Scholar 

  7. Northcott PA et al (2019) Medulloblastoma. Nat Rev Dis Primers 5(1):11

    Article  PubMed  Google Scholar 

  8. Hammoud H et al (2020) Drug repurposing in medulloblastoma: challenges and recommendations. Curr Treat Options Oncol 22(1):6

    Article  PubMed  Google Scholar 

  9. Dirven L et al (2020) Neurocognitive functioning and health-related quality of life in adult medulloblastoma patients: long-term outcomes of the NOA-07 study. J Neurooncol 148(1):117–130

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wang Y, Levy DE (2012) Comparative evolutionary genomics of the STAT family of transcription factors. Jakstat 1(1):23–33

    PubMed  PubMed Central  Google Scholar 

  11. Chakraborty D et al (2017) Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis. Nat Commun 8(1):1130

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gu Y, Mohammad IS, Liu Z (2020) Overview of the STAT-3 signaling pathway in cancer and the development of specific inhibitors. Oncol Lett 19(4):2585–2594

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Piperi C, Papavassiliou KA, Papavassiliou AG (2019) Pivotal role of STAT3 in shaping glioblastoma immune microenvironment. Cells 8(11):1398

    Article  CAS  PubMed Central  Google Scholar 

  14. Alonzi T et al (2001) Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene inactivation in the liver. Mol Cell Biol 21(5):1621–1632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Benito C et al (2017) STAT3 Controls the long-term survival and phenotype of repair schwann cells during nerve regeneration. J Neurosci 37(16):4255–4269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Huang C et al (2008) JAK2-STAT3 signaling pathway mediates thrombin-induced proinflammatory actions of microglia in vitro. J Neuroimmunol 204(1–2):118–125

    Article  CAS  PubMed  Google Scholar 

  17. Wen Z, Darnell JE Jr (1997) Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3. Nucleic Acids Res 25(11):2062–2067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tkach M et al (2013) p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth. Endocr Relat Cancer 20(2):197–212

    Article  CAS  PubMed  Google Scholar 

  19. Wu M et al (2019) Negative regulators of STAT3 signaling pathway in cancers. Cancer Manag Res 11:4957–4969

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dong Y et al (2010) Cucurbitacin E, a tetracyclic triterpenes compound from Chinese medicine, inhibits tumor angiogenesis through VEGFR2-mediated Jak2-STAT3 signaling pathway. Carcinogenesis 31(12):2097–2104

    Article  CAS  PubMed  Google Scholar 

  21. Floss DM et al (2013) Identification of canonical tyrosine-dependent and non-canonical tyrosine-independent STAT3 activation sites in the intracellular domain of the interleukin 23 receptor. J Biol Chem 288(27):19386–19400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Timofeeva OA et al (2012) Mechanisms of unphosphorylated STAT3 transcription factor binding to DNA. J Biol Chem 287(17):14192–14200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang X et al (2007) Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Proc Natl Acad Sci U S A 104(10):4060–4064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rozovski U et al (2018) STAT3 is constitutively acetylated on lysine 685 residues in chronic lymphocytic leukemia cells. Oncotarget 9(72):33710–33718

    Article  PubMed  PubMed Central  Google Scholar 

  25. Xu YS et al (2016) STAT3 Undergoes acetylation-dependent mitochondrial translocation to regulate pyruvate metabolism. Sci Rep 6:39517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yang J et al (2010) Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc Natl Acad Sci U S A 107(50):21499–21504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dasgupta M et al (2015) STAT3-driven transcription depends upon the dimethylation of K49 by EZH2. Proc Natl Acad Sci U S A 112(13):3985–3990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Murase S (2013) Signal transducer and activator of transcription 3 (STAT3) degradation by proteasome controls a developmental switch in neurotrophin dependence. J Biol Chem 288(28):20151–20161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wei J et al (2012) The ubiquitin ligase TRAF6 negatively regulates the JAK-STAT signaling pathway by binding to STAT3 and mediating its ubiquitination. PLoS ONE 7(11):e49567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Su F et al (2012) Protein tyrosine phosphatase Meg2 dephosphorylates signal transducer and activator of transcription 3 and suppresses tumor growth in breast cancer. Breast Cancer Res 14(2):R38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li C et al (2016) SHP2, SOCS3 and PIAS3 expression patterns in medulloblastomas: relevance to STAT3 activation and resveratrol-suppressed STAT3 signaling. Nutrients. https://doi.org/10.3390/nu9010003

    Article  PubMed  PubMed Central  Google Scholar 

  32. Woetmann A et al (1999) Inhibition of protein phosphatase 2A induces serine/threonine phosphorylation, subcellular redistribution, and functional inhibition of STAT3. Proc Natl Acad Sci USA 96(19):10620–10625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nicholson SE et al (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 USA 97(12):6493–6498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chung CD et al (1997) Specific inhibition of Stat3 signal transduction by PIAS3. Science 278(5344):1803–1805

    Article  CAS  PubMed  Google Scholar 

  35. De-Fraja C et al (1998) Members of the JAK/STAT proteins are expressed and regulated during development in the mammalian forebrain. J Neurosci Res 54(3):320–330

    Article  CAS  PubMed  Google Scholar 

  36. Zhong Z, Wen Z, Darnell JE Jr (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264(5155):95–98

    Article  CAS  PubMed  Google Scholar 

  37. Dziennis S, Alkayed NJ (2008) Role of signal transducer and activator of transcription 3 in neuronal survival and regeneration. Rev Neurosci 19(4–5):341–361

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Takeda K et al (1997) Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci USA 94(8):3801–3804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Foshay KM, Gallicano GI (2008) Regulation of Sox2 by STAT3 initiates commitment to the neural precursor cell fate. Stem Cells Dev 17(2):269–278

    Article  CAS  PubMed  Google Scholar 

  40. Kanski R et al (2014) A star is born: new insights into the mechanism of astrogenesis. Cell Mol Life Sci 71(3):433–447

    Article  CAS  PubMed  Google Scholar 

  41. Ma X et al (2017) Stat3 controls maturation and terminal differentiation in mouse hippocampal neurons. J Mol Neurosci 61(1):88–95

    Article  CAS  PubMed  Google Scholar 

  42. Nicolas CS et al (2012) The Jak/STAT pathway is involved in synaptic plasticity. Neuron 73(2):374–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. McGregor G, Irving AJ, Harvey J (2017) Canonical JAK-STAT signaling is pivotal for long-term depression at adult hippocampal temporoammonic-CA1 synapses. Faseb j 31(8):3449–3466

    Article  CAS  PubMed  Google Scholar 

  44. Murata S et al (2000) Occurrence of a transcription factor, signal transducer and activators of transcription 3 (Stat3), in the postsynaptic density of the rat brain. Brain Res Mol Brain Res 78(1–2):80–90

    Article  CAS  PubMed  Google Scholar 

  45. Sahin GS et al (2020) Leptin stimulates synaptogenesis in hippocampal neurons via KLF4 and SOCS3 inhibition of STAT3 signaling. Mol Cell Neurosci 106:103500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wan HL et al (2021) STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer’s disease animal model. Theranostics 11(11):5511–5524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jung JE et al (2009) Regulation of Mn-superoxide dismutase activity and neuroprotection by STAT3 in mice after cerebral ischemia. J Neurosci 29(21):7003–7014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dziennis S et al (2007) Role of signal transducer and activator of transcription-3 in estradiol-mediated neuroprotection. J Neurosci 27(27):7268–7274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Murase S et al (2012) Loss of signal transducer and activator of transcription 3 (STAT3) signaling during elevated activity causes vulnerability in hippocampal neurons. J Neurosci 32(44):15511–15520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wan J et al (2010) Tyk2/STAT3 signaling mediates beta-amyloid-induced neuronal cell death: implications in Alzheimer’s disease. J neurosci 30(20):6873–6881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bian Z et al (2021) Noncoding RNAs involved in the STAT3 pathway in glioma. Cancer Cell Int 21(1):445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yang F et al (2010) Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor cells by inhibiting STAT3 and AKT signaling pathways. Mol Cancer Res 8(1):35–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bhoopathi P et al (2011) SPARC stimulates neuronal differentiation of medulloblastoma cells via the Notch1/STAT3 pathway. Cancer Res 71(14):4908–4919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Pan L et al (2021) STAT3 inhibitor in combination with irradiation significantly inhibits cell viability, cell migration, invasion and tumorsphere growth of human medulloblastoma cells. Cancer Biol Ther 22(7–9):430–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ball S et al (2011) The small molecule, LLL12, inhibits STAT3 phosphorylation and induces apoptosis in medulloblastoma and glioblastoma cells. PLoS ONE 6(4):e18820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chen X et al (2018) Blocking interleukin-6 signaling inhibits cell viability/proliferation, glycolysis, and colony forming activity of human medulloblastoma cells. Int J Oncol 52(2):571–578

    CAS  PubMed  Google Scholar 

  57. Kotipatruni RR et al (2012) Apoptosis induced by knockdown of uPAR and MMP-9 is mediated by inactivation of EGFR/STAT3 signaling in medulloblastoma. PLoS ONE 7(9):e44798

    Article  PubMed  PubMed Central  Google Scholar 

  58. White CL et al (2019) A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog medulloblastoma. Cancers 11(11):1702

    Article  CAS  PubMed Central  Google Scholar 

  59. Gao P et al (2017) The roles of signal transducer and activator of transcription factor 3 in tumor angiogenesis. Oncotarget 8(40):69139–69161

    Article  PubMed  PubMed Central  Google Scholar 

  60. Niu G et al (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21(13):2000–2008

    Article  CAS  PubMed  Google Scholar 

  61. Craveiro RB et al (2017) The anti-neoplastic activity of vandetanib against high-risk medulloblastoma variants is profoundly enhanced by additional PI3K inhibition. Oncotarget 8(29):46915–46927

    Article  PubMed  PubMed Central  Google Scholar 

  62. Wang T et al (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10(1):48–54

    Article  PubMed  Google Scholar 

  63. Abad C et al (2014) Targeted STAT3 disruption in myeloid cells alters immunosuppressor cell abundance in a murine model of spontaneous medulloblastoma. J Leukoc Biol 95(2):357–367

    Article  PubMed  PubMed Central  Google Scholar 

  64. Kumar V et al (2016) CD45 Phosphatase Inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity 44(2):303–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Purvis IJ et al (2020) B7H3 in medulloblastoma-derived exosomes A novel tumorigenic role. Int J Mol Sci. https://doi.org/10.3390/ijms21197050

    Article  PubMed  PubMed Central  Google Scholar 

  66. Molina-Peña R, Tudon-Martinez JC, Aquines-Gutiérrez O (2020) A mathematical model of average dynamics in a stem cell hierarchy suggests the combinatorial targeting of cancer stem cells and progenitor cells as a potential strategy against tumor growth. Cancers (Basel). https://doi.org/10.3390/cancers12092590

    Article  Google Scholar 

  67. Bahmad HF, Poppiti RJ (2020) Medulloblastoma cancer stem cells: molecular signatures and therapeutic targets. J Clin Pathol 73(5):243–249

    Article  CAS  PubMed  Google Scholar 

  68. Liu H et al (2020) Necroptotic astrocytes contribute to maintaining stemness of disseminated medulloblastoma through CCL2 secretion. Neuro Oncol 22(5):625–638

    Article  CAS  PubMed  Google Scholar 

  69. Nazio F et al (2021) Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling. Acta Neuropathol 142(3):537–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Garg N et al (2017) CD133 (+) brain tumor-initiating cells are dependent on STAT3 signaling to drive medulloblastoma recurrence. Oncogene 36(5):606–617

    Article  CAS  PubMed  Google Scholar 

  71. Chang CJ et al (2012) Inhibition of phosphorylated STAT3 by cucurbitacin I enhances chemoradiosensitivity in medulloblastoma-derived cancer stem cells. Childs Nerv Syst 28(3):363–373

    Article  PubMed  Google Scholar 

  72. Sreenivasan L et al (2020) Autocrine IL-6/STAT3 signaling aids development of acquired drug resistance in Group 3 medulloblastoma. Cell Death Dis 11(12):1035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Craveiro RB et al (2014) In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promising in vitro and in vivo efficacy. Oncotarget 5(16):7149–7161

    Article  PubMed  PubMed Central  Google Scholar 

  74. Liu L et al (2006) Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66(24):11851–11858

    Article  CAS  PubMed  Google Scholar 

  75. Yang F et al (2008) Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas. Mol Cancer Ther 7(11):3519–3526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Brave SR et al (2011) Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer. Int J Oncol 39(1):271–278

    CAS  PubMed  Google Scholar 

  77. Ehrhardt M et al (2018) The FDA approved PI3K inhibitor GDC-0941 enhances in vitro the anti-neoplastic efficacy of Axitinib against c-myc-amplified high-risk medulloblastoma. J Cell Mol Med 22(4):2153–2161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mendel DB et al (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9(1):327–337

    CAS  PubMed  Google Scholar 

  79. Ray S et al (2018) Suppression of STAT3 NH(2) -terminal domain chemosensitizes medulloblastoma cells by activation of protein inhibitor of activated STAT3 via de-repression by microRNA-21. Mol Carcinog 57(4):536–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Schust J et al (2006) Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol 13(11):1235–1242

    Article  CAS  PubMed  Google Scholar 

  81. Chen X et al (2021) LLL12B, a small molecule STAT3 inhibitor, induces growth arrest, apoptosis, and enhances cisplatin-mediated cytotoxicity in medulloblastoma cells. Sci Rep 11(1):6517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Xiao H et al (2015) A novel small molecular STAT3 inhibitor, LY5, inhibits cell viability, cell migration, and angiogenesis in medulloblastoma cells. J Biol Chem 290(6):3418–3429

    Article  CAS  PubMed  Google Scholar 

  83. Sreenivasan L et al (2022) Targeting the gp130/STAT3 Axis Attenuates tumor microenvironment mediated chemoresistance in group 3 medulloblastoma cells. Cells 11(3):381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jiao Y et al (2015) Resveratrol inhibits the invasion of glioblastoma-initiating cells via down-regulation of the PI3K/Akt/NF-κB signaling pathway. Nutrients 7(6):4383–4402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Mokni M et al (2007) Effect of resveratrol on antioxidant enzyme activities in the brain of healthy rat. Neurochem Res 32(6):981–987

    Article  CAS  PubMed  Google Scholar 

  86. Yu LJ et al (2008) Inhibition of STAT3 expression and signaling in resveratrol-differentiated medulloblastoma cells. Neoplasia 10(7):736–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wang Q et al (2003) Resveratrol promotes differentiation and induces Fas-independent apoptosis of human medulloblastoma cells. Neurosci Lett 351(2):83–86

    Article  CAS  PubMed  Google Scholar 

  88. Lu K-H et al (2009) Evaluation of radiotherapy effect in resveratrol-treated medulloblastoma cancer stem-like cells. Childs Nerv Syst 25(5):543–550

    Article  PubMed  Google Scholar 

  89. Lee SJ et al (2011) Curcumin-induced HDAC inhibition and attenuation of medulloblastoma growth in vitro and in vivo. BMC Cancer 11(1):144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lim KJ et al (2011) A polymeric nanoparticle formulation of curcumin inhibits growth, clonogenicity and stem-like fraction in malignant brain tumors. Cancer Biol Ther 11(5):464–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Elamin MH et al (2010) Curcumin inhibits the sonic hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells. Mol Carcinog 49(3):302–314

    Article  CAS  PubMed  Google Scholar 

  92. He M et al (2014) Curcumin suppresses cell proliferation through inhibition of the Wnt/β-catenin signaling pathway in medulloblastoma. Oncol Rep 32(1):173–180

    Article  CAS  PubMed  Google Scholar 

  93. Xu XT et al (2017) Celecoxib enhances the radiosensitivity of HCT116 cells in a COX-2 independent manner by up-regulating BCCIP. Am J Transl Res 9(3):1088–1100

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Liu DB et al (2012) Celecoxib induces apoptosis and cell-cycle arrest in nasopharyngeal carcinoma cell lines via inhibition of STAT3 phosphorylation. Acta Pharmacol Sin 33(5):682–690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Yang MY et al (2014) Celecoxib suppresses the phosphorylation of STAT3 protein and can enhance the radiosensitivity of medulloblastoma-derived cancer stem-like cells. Int J Mol Sci 15(6):11013–11029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. el Dakir H et al (2018) The anti-psychotic drug pimozide is a novel chemotherapeutic for breast cancer. Oncotarget 9(79):34889–34910

    Article  PubMed Central  Google Scholar 

  97. Zhou W et al (2016) The antipsychotic drug pimozide inhibits cell growth in prostate cancer through suppression of STAT3 activation. Int J Oncol 48(1):322–328

    Article  CAS  PubMed  Google Scholar 

  98. Ranjan A, Kaushik I, Srivastava SK (2020) Pimozide suppresses the growth of brain tumors by targeting STAT3-mediated autophagy. Cells. https://doi.org/10.3390/cells9092141

    Article  PubMed  PubMed Central  Google Scholar 

  99. Rahaman SO et al (2002) Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene 21(55):8404–8413

    Article  CAS  PubMed  Google Scholar 

  100. Han ES et al (2018) Ruxolitinib synergistically enhances the anti-tumor activity of paclitaxel in human ovarian cancer. Oncotarget 9(36):24304–24319

    Article  PubMed  PubMed Central  Google Scholar 

  101. Ando S et al (2016) Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells. Oncotarget 7(47):76793–76805

    Article  PubMed  PubMed Central  Google Scholar 

  102. Haile WB et al (2016) The janus kinase inhibitor ruxolitinib reduces HIV replication in human macrophages and ameliorates HIV encephalitis in a murine model. Neurobiol Dis 92(Pt B):137–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wei J et al (2019) Targeting upstream kinases of STAT3 in human MEDULLOBLASTOMA cells. Curr Cancer Drug Targets 19(7):571–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Blaskovich MA et al (2003) 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 Res 63(6):1270–1279

    CAS  PubMed  Google Scholar 

  105. Lo HW et al (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(19):6042–6054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Garcia R et al (2001) Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 20(20):2499–2513

    Article  CAS  PubMed  Google Scholar 

  107. Siddiquee K et al (2007) Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci USA 104(18):7391–7396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ferrajoli A et al (2007) WP1066 disrupts Janus kinase-2 and induces caspase-dependent apoptosis in acute myelogenous leukemia cells. Cancer Res 67(23):11291–11299

    Article  CAS  PubMed  Google Scholar 

  109. Groot J et al (2022) A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma. CNS Oncol. https://doi.org/10.2217/cns-2022-0005

    Article  PubMed  PubMed Central  Google Scholar 

  110. Mandal T et al (2014) Reduced phosphorylation of Stat3 at Ser-727 mediated by casein kinase 2—protein phosphatase 2A enhances Stat3 Tyr-705 induced tumorigenic potential of glioma cells. Cell Signal 26(8):1725–1734

    Article  CAS  PubMed  Google Scholar 

  111. D’Arcy BM et al (2019) The antitumor drug LB-100 Is a catalytic inhibitor of protein phosphatase 2A (PPP2CA) and 5 (PPP5C) coordinating with the active-site catalytic metals in PPP5C. Mol Cancer Ther 18(3):556–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ho WS et al (2016) PP2A inhibition with LB100 enhances cisplatin cytotoxicity and overcomes cisplatin resistance in medulloblastoma cells. Oncotarget 7(11):12447–12463

    Article  PubMed  PubMed Central  Google Scholar 

  113. Jagadeesan S, Hakkim A (2018) RNAi Screening: automated high-throughput liquid RNAI screening in caenorhabditis elegans. Curr Protoc Mol Biol 124(1):e65

    Article  PubMed  PubMed Central  Google Scholar 

  114. Di Silvio D et al (2019) Self-assembly of poly(allylamine)/siRNA nanoparticles, their intracellular fate and siRNA delivery. J Colloid Interface Sci 557:757–766

    Article  PubMed  Google Scholar 

  115. Kulakova A et al (2020) Albumin-neprilysin fusion protein: understanding stability using small angle X-ray scattering and molecular dynamic simulations. Sci Rep 10(1):10089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Marsh JA et al (2013) Protein complexes are under evolutionary selection to assemble via ordered pathways. Cell 153(2):461–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Rafei M et al (2011) A MCP1 fusokine with CCR2-specific tumoricidal activity. Mol Cancer 10:121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chlenski A et al (2006) SPARC expression is associated with impaired tumor growth, inhibited angiogenesis and changes in the extracellular matrix. Int J Cancer 118(2):310–316

    Article  CAS  PubMed  Google Scholar 

  119. Chetty C et al (2012) SPARC expression induces cell cycle arrest via STAT3 signaling pathway in medulloblastoma cells. Biochem Biophys Res Commun 417(2):874–879

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Not funded.

Author information

Author notes

  1. Anwar Zaiter, Zahraa F. Audi, Fatima Shawraba and Zahraa Saker these authors have contributed equally to this work as co-first authors.

Authors and Affiliations

  1. Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon

    Anwar Zaiter, Zahraa F. Audi, Fatima Shawraba, Zahraa Saker, Hayat Harati & Sanaa M. Nabha

  2. Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, 33140, USA

    Hisham F. Bahmad

  3. Oradea Medical University, Oradea, Romania

    Rami H. Nabha

Authors
  1. Anwar Zaiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zahraa F. Audi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fatima Shawraba
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zahraa Saker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hisham F. Bahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rami H. Nabha
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hayat Harati
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sanaa M. Nabha
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AZ and SN conceived the concept and idea of the present review. AZ and SN worked on the study design strategy and selected the topics to be discussed. AZ, ZA, FS, ZS, RN and HB did literature searches and screened titles and abstracts for relevance. AZ, ZA, FS and ZS abstracted the data from the eligible full text articles, analyzed and interpreted the data and drafted the manuscript. HH, RN and HB revised the final draft of the manuscript. SN critically revised the manuscript with input from the entire team. All authors have read and approved the final draft.

Corresponding author

Correspondence to Sanaa M. Nabha.

Ethics declarations

Conflict of interest

None.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zaiter, A., Audi, Z.F., Shawraba, F. et al. STAT3 in medulloblastoma: a key transcriptional regulator and potential therapeutic target. Mol Biol Rep 49, 10635–10652 (2022). https://doi.org/10.1007/s11033-022-07694-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-022-07694-6

Keywords

Search

Navigation