Role of STAT3 in Pancreatic Cancer: A Target for Therapy

  • Waaqo B. Daddacha
  • Allyson E. Koyen
  • Ashley J. Schlafstein
  • David S. Yu
Chapter
First Online:

Abstract

STAT3 is a member of the signal transducer and activator of transcription (STAT) family of proteins. Activation of the STAT3 signaling cascade results in the transcription of several pro-proliferative and anti-apoptotic proteins. STAT3 is also a potent modulator of the immune system, and its activation results in the suppression of the immune response. Dysregulation of STAT3 is implicated in the development and progression of a number of malignancies, including pancreatic ductal adenocarcinoma. Because of its involvement in tumorigenesis and the evasion of the immune response, STAT3 is emerging as a potential therapeutic target for pancreatic cancer, with several therapies currently under development.

Keywords

Pancreatic cancer STAT3 Immunotherapy 
This is a preview of subscription content, log in to check access

References

  1. 1.
    Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67(1):7–30PubMedCrossRefGoogle Scholar
  2. 2.
    Zambirinis CP et al (2014) Pancreatic cancer, inflammation, and microbiome. Cancer J 20(3):195–202PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Grimley PM, Dong F, Rui H (1999) Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation. Cytokine Growth Factor Rev 10(2):131–157PubMedCrossRefGoogle Scholar
  4. 4.
    Miklossy G, Hilliard TS, Turkson J (2013) Therapeutic modulators of STAT signalling for human diseases. Nat Rev Drug Discov 12(8):611–629PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    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(8):984–994PubMedCrossRefGoogle Scholar
  6. 6.
    Darnell JE Jr (1997) STATs and gene regulation. Science 277(5332):1630–1635PubMedCrossRefGoogle Scholar
  7. 7.
    Gorissen M et al (2011) STAT genes display differential evolutionary rates that correlate with their roles in the endocrine and immune system. J Endocrinol 209(2):175–184PubMedCrossRefGoogle Scholar
  8. 8.
    Gao Q et al (2004) Identification of the linker-SH2 domain of STAT as the origin of the SH2 domain using two-dimensional structural alignment. Mol Cell Proteomics 3(7):704–714PubMedCrossRefGoogle Scholar
  9. 9.
    Wen Z, Zhong Z, Darnell JE Jr (1995) Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82(2):241–250PubMedCrossRefGoogle Scholar
  10. 10.
    Scholz A et al (2003) Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology 125(3):891–905PubMedCrossRefGoogle Scholar
  11. 11.
    Kortylewski M et al (2005) Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11(12):1314–1321PubMedCrossRefGoogle Scholar
  12. 12.
    Zorn E et al (2006) IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108(5):1571–1579PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Zhao S et al (2008) Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Res 68(11):4221–4228PubMedCrossRefGoogle Scholar
  14. 14.
    Qiu Z et al (2007) RNA interference-mediated signal transducers and activators of transcription 3 gene silencing inhibits invasion and metastasis of human pancreatic cancer cells. Cancer Sci 98(7):1099–1106PubMedCrossRefGoogle Scholar
  15. 15.
    Sahu RP, Srivastava SK (2009) The role of STAT-3 in the induction of apoptosis in pancreatic cancer cells by benzyl isothiocyanate. J Natl Cancer Inst 101(3):176–193PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Denley SM et al (2013) Activation of the IL-6R/Jak/stat pathway is associated with a poor outcome in resected pancreatic ductal adenocarcinoma. J Gastrointest Surg 17(5):887–898PubMedCrossRefGoogle Scholar
  17. 17.
    Wang X et al (2009) Expression of IL-23 and IL-17 and effect of IL-23 on IL-17 production in ankylosing spondylitis. Rheumatol Int 29(11):1343–1347PubMedCrossRefGoogle Scholar
  18. 18.
    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):95–98PubMedCrossRefGoogle Scholar
  19. 19.
    Yu H et al (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14(11):736–746PubMedCrossRefGoogle Scholar
  20. 20.
    Carpenter RL, Lo HW (2014) STAT3 target genes relevant to human cancers. Cancers (Basel) 6(2):897–925CrossRefGoogle Scholar
  21. 21.
    Nair RR, Tolentino JH, Hazlehurst LA (2012) Role of STAT3 in transformation and drug resistance in CML. Front Oncol 2:30PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Li Y et al (2007) Activation of the signal transducers and activators of the transcription 3 pathway in alveolar epithelial cells induces inflammation and adenocarcinomas in mouse lung. Cancer Res 67(18):8494–8503PubMedCrossRefGoogle Scholar
  23. 23.
    Hirano T, Ishihara K, Hibi M (2000) Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19(21):2548–2556PubMedCrossRefGoogle Scholar
  24. 24.
    Ding BB et al (2008) Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood 111(3):1515–1523PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Fukada T et al (1996) Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5(5):449–460PubMedCrossRefGoogle Scholar
  26. 26.
    Glienke W, Hausmann E, Bergmann L (2011) Downregulation of STAT3 signaling induces apoptosis but also promotes anti-apoptotic gene expression in human pancreatic cancer cell lines. Tumour Biol 32(3):493–500PubMedCrossRefGoogle Scholar
  27. 27.
    Xiong H et al (2008) Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia 10(3):287–297PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Shirogane T et al (1999) Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity 11(6):709–719PubMedCrossRefGoogle Scholar
  29. 29.
    Niu G et al (2005) Role of Stat3 in regulating p53 expression and function. Mol Cell Biol 25(17):7432–7440PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Corcoran RB et al (2011) STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res 71(14):5020–5029PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Epling-Burnette PK et al (2001) Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest 107(3):351–362PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Rahaman SO et al (2002) Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene 21(55):8404–8413PubMedCrossRefGoogle Scholar
  33. 33.
    Wachsmann MB, Pop LM, Vitetta ES (2012) Pancreatic ductal adenocarcinoma: a review of immunologic aspects. J Investig Med 60(4):643–663PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Mace TA et al (2013) Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res 73(10):3007–3018PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Wei D et al (2003) Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22(3):319–329PubMedCrossRefGoogle Scholar
  36. 36.
    Takeda K et al (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10(1):39–49PubMedCrossRefGoogle Scholar
  37. 37.
    Cheng F et al (2003) A critical role for Stat3 signaling in immune tolerance. Immunity 19(3):425–436PubMedCrossRefGoogle Scholar
  38. 38.
    Sasaki K et al (2008) Stat6 signaling suppresses VLA-4 expression by CD8+ T cells and limits their ability to infiltrate tumor lesions in vivo. J Immunol 181(1):104–108PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Steeg PS (2005) Cancer biology: emissaries set up new sites. Nature 438(7069):750–751PubMedCrossRefGoogle Scholar
  40. 40.
    Deng J et al (2012) S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites. Cancer Cell 21(5):642–654PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Zhang W et al (2013) Myeloid clusters are associated with a pro-metastatic environment and poor prognosis in smoking-related early stage non-small cell lung cancer. PLoS One 8(5):e65121PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Lin L et al (2010) Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells. Cancer Res 70(6):2445–2454PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Lin L et al (2016) STAT3 as a potential therapeutic target in ALDH+ and CD44+/CD24+ stem cell-like pancreatic cancer cells. Int J Oncol 49(6):2265–2274PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Hu Y et al (2017) A novel STAT3 inhibitor HO-3867 induces cell apoptosis by reactive oxygen species-dependent endoplasmic reticulum stress in human pancreatic cancer cells. Anti-Cancer Drugs 28(4):392–400PubMedCrossRefGoogle Scholar
  45. 45.
    Rabi T, Catapano CV (2016) Aphanin, a triterpenoid from Amoora rohituka inhibits K-Ras mutant activity and STAT3 in pancreatic carcinoma cells. Tumour Biol 37(9):12455–12464PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd 2017

Authors and Affiliations

  • Waaqo B. Daddacha
    • 1
  • Allyson E. Koyen
    • 1
  • Ashley J. Schlafstein
    • 1
  • David S. Yu
    • 1
  1. 1.Department of Radiation OncologyEmory University School of MedicineAtlantaUSA

Personalised recommendations