Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Curcumin and Genistein Role in Regulation of STAT-3 in Pancreatic Cancer

  • Chapter
  • First Online:
Role of Transcription Factors in Gastrointestinal Malignancies

Abstract

Pancreatic cancer (PC) is one of the most fatal malignant tumors across the world. STAT-3 is involved in PC growth and metastasis. STAT-3 is a transcription factor that regulates many oncogenic transduction pathways. In the current chapter, we discuss the importance of STAT-3 in hypoxia and hypoxia-inducible genes. Further, we also explore the inhibition of STAT-3 by phytochemicals such as curcumin and genistein.

The original version of this chapter was revised. The book was inadvertently published without Abstracts and Keywords, which are now included in all the chapters. An erratum to this chapter can be found at https://doi.org/10.1007/978-981-10-6728-0_39

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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

  1. Alfranca A, Gutiérrez MD, Vara A, Aragonés J, Vidal F, Landázuri MO (2002) c-Jun and hypoxia-inducible factor 1 functionally cooperate in hypoxia-induced gene transcription. Mol Cell Biol 22:12–22

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Alvarez-Tejado M, Alfranca A, Aragonés J, Vara A, Landázuri MO, del Peso L (2002) Lack of evidence for the involvement of the phosphoinositide 3-kinase/Akt pathway in the activation of hypoxia-inducible factors by low oxygen tension. J Biol Chem 277:13508–13517

    Article  PubMed  CAS  Google Scholar 

  3. Bromberg JF, Horvath CM, Wen Z, Schreiber RD, Darnell JE (1996) Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma. Proc Natl Acad Sci 93:7673–7678

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Gouilleux-Gruart V, Gouilleux F, Desaint C, Claisse J, Capiod J-C, Delobel J, Weber-Nordt R, Dusanter-Fourt I, Dreyfus F, Groner B (1996) STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients. Blood 87:1692–1697

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, Johnson DE, Huang L, He Y, Kim JD (2000) Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci 97:4227–4232

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, Cox CE, Falcone R, Fairclough R, Parsons S (2001) Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 20:2499–2513

    Article  PubMed  CAS  Google Scholar 

  9. Watson C, Miller W (1995) Elevated levels of members of the STAT family of transcription factors in breast carcinoma nuclear extracts. Br J Cancer 71:840–844

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger W, 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 98:7319–7324

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21:2000–2008

    Article  CAS  PubMed  Google Scholar 

  12. Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL (2003) Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22:319–329

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Fujita DJ, Ethier SP (1997) Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ 8:1267

    PubMed  Google Scholar 

  15. Grandis JR, Drenning SD, Chakraborty A, Zhou M-Y, Zeng Q, Pitt AS, Tweardy DJ (1998) Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor-mediated cell growth in vitro. J Clin Investig 102:1385

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. 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 

  17. Yu C-L, 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 

  18. Funamoto M, Fujio Y, Kunisada K, Negoro S, Tone E, Osugi T, Hirota H, Izumi M, Yoshizaki K, Walsh K (2000) Signal transducer and activator of transcription 3 is required for glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes. J Biol Chem 275:10561–10566

    Article  PubMed  CAS  Google Scholar 

  19. Wei L-H, Kuo M-L, Chen C-A, Chou C-H, Lai K-B, Lee C-N, Hsieh C-Y (2003) Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene 22:1517–1527

    Article  PubMed  CAS  Google Scholar 

  20. Dechow TN, Pedranzini L, Leitch A, Leslie K, Gerald WL, Linkov I, Bromberg JF (2004) Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc Natl Acad Sci U S A 101:10602–10607

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. McCawley LJ, Matrisian LM (2001) Matrix metalloproteinases: they’re not just for matrix anymore! Curr Opin Cell Biol 13:534–540

    Article  PubMed  CAS  Google Scholar 

  22. Xie T-x, Wei D, Liu M, Gao AC, Ali-Osman F, Sawaya R, Huang S (2004) Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 23:3550–3560

    Article  CAS  PubMed  Google Scholar 

  23. Yahata Y, Shirakata Y, Tokumaru S, Yamasaki K, Sayama K, Hanakawa Y, Detmar M, Hashimoto K (2003) Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation. J Biol Chem 278:40026–40031

    Article  CAS  PubMed  Google Scholar 

  24. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT (2000) Mechanisms of signal transduction-reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1a during hypoxia. A mechanism of O2 sensing. J Biol Chem 275:25130–25138

    Article  PubMed  CAS  Google Scholar 

  25. Hirota K, Semenza GL (2001) Rac1 activity is required for the activation of hypoxia-inducible factor 1. J Biol Chem 276:21166–21172

    Article  PubMed  CAS  Google Scholar 

  26. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu M-M, Simons JW, Semenza GL (2000) Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60:1541–1545

    CAS  PubMed  Google Scholar 

  27. Arsham AM, Plas DR, Thompson CB, Simon MC (2002) Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1α nor sufficient for HIF-1-dependent target gene transcription. J Biol Chem 277:15162–15170

    Article  PubMed  CAS  Google Scholar 

  28. Beitner-Johnson D, Rust RT, Hsieh TC, Millhorn DE (2001) Hypoxia activates Akt and induces phosphorylation of GSK-3 in PC12 cells. Cell Signal 13:23–27

    Article  PubMed  CAS  Google Scholar 

  29. Jones A, Fujiyama C, Blanche C, Moore JW, Fuggle S, Cranston D, Bicknell R, Harris AL (2001) Relation of vascular endothelial growth factor production to expression and regulation of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α in human bladder tumors and cell lines. Clin Cancer Res 7:1263–1272

    PubMed  CAS  Google Scholar 

  30. Gray MJ, Zhang J, Ellis LM, Semenza GL, Evans DB, Watowich SS, Gallick GE (2005) HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene 24:3110–3120

    Article  PubMed  CAS  Google Scholar 

  31. Namiki A, Brogi E, Kearney M, Kim EA, Wu T, Couffinhal T, Varticovski L, Isner JM (1995) Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells. J Biol Chem 270:31189–31195

    Article  PubMed  CAS  Google Scholar 

  32. Jiang B-H, Agani F, Passaniti A, Semenza GL (1997) V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res 57:5328–5335

    CAS  PubMed  Google Scholar 

  33. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312

    Article  CAS  PubMed  Google Scholar 

  34. Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, Iyer N, LaRusch J, Pak B, Taghavi P (2003) Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 63:1138–1143

    CAS  PubMed  Google Scholar 

  35. Alvarez-Tejado M, Naranjo-Suárez S, Jiménez C, Carrera AC, Landázuri MO, del Peso L (2001) Hypoxia induces the activation of the phosphatidylinositol 3-kinase/Akt cell survival pathway in PC12 cells protective role in apoptosis. J Biol Chem 276:22368–22374

    Article  CAS  PubMed  Google Scholar 

  36. Chen EY, Mazure NM, Cooper JA, Giaccia AJ (2001) Hypoxia activates a platelet-derived growth factor receptor/phosphatidylinositol 3-kinase/Akt pathway that results in glycogen synthase kinase-3 inactivation. Cancer Res 61:2429–2433

    CAS  PubMed  Google Scholar 

  37. Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB (2000) Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 14:391–396

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Blancher C, Moore JW, Robertson N, Harris AL (2001) Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1α, HIF-2α, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3′-kinase/Akt signaling pathway. Cancer Res 61:7349–7355

    CAS  PubMed  Google Scholar 

  39. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21:3995–4004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Mukhopadhyay A, Banerjee S, Stafford LJ, Xia C, Liu M, Aggarwal BB (2002) Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation. Oncogene 21:8852

    Article  PubMed  CAS  Google Scholar 

  41. Hsieh F-C, Cheng G, Lin J (2005) Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun 335:292–299

    Article  PubMed  CAS  Google Scholar 

  42. Satoh K, Kaneko K, Hirota M, Masamune A, Satoh A, Shimosegawa T (2001) Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumors. Cancer 92:271–278

    Article  PubMed  CAS  Google Scholar 

  43. Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D (2006) Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12:11–19

    Article  PubMed  CAS  Google Scholar 

  44. Schust J, Sperl B, Hollis A, Mayer TU, Berg T (2006) Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol 13:1235–1242

    Article  PubMed  CAS  Google Scholar 

  45. Anto RJ, Mukhopadhyay A, Denning K, Aggarwal BB (2002) Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carcinogenesis 23:143–150

    Article  PubMed  CAS  Google Scholar 

  46. Glienke W, Maute L, Wicht J, Bergmann L (2009) Curcumin inhibits constitutive STAT3 phosphorylation in human pancreatic cancer cell lines and downregulation of survivin/BIRC5 gene expression. Cancer Investig 28:166–171

    Article  Google Scholar 

  47. Kunnumakkara AB, Anand P, Aggarwal BB (2008) Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett 269:199–225

    Article  PubMed  CAS  Google Scholar 

  48. Fiala M (2015) Curcumin and omega-3 fatty acids enhance NK cell-induced apoptosis of pancreatic cancer cells but curcumin inhibits interferon-γ production: benefits of omega-3 with curcumin against cancer. Molecules 20:3020–3026

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  50. Glienke W, Maute L, Wicht J, Bergmann L (2009) Wilms’ tumour gene 1 (WT1) as a target in curcumin treatment of pancreatic cancer cells. Eur J Cancer 45:874–880

    Article  PubMed  CAS  Google Scholar 

  51. Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S-i, Itoh N, Shibuya M, Fukami Y (1987) Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 262:5592–5595

    PubMed  CAS  Google Scholar 

  52. Turkson J, Jove R (2000) STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 19:6613

    Article  PubMed  CAS  Google Scholar 

  53. Banerjee S, Li Y, Wang Z, Sarkar FH (2008) Multi-targeted therapy of cancer by genistein. Cancer Lett 269:226–242

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK (2012) Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets 16:15–31

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Suzuki R, Kang YA, Li X, Roife D, Zhang R, Fleming JB (2014) Genistein potentiates the antitumor effect of 5-fluorouracil by inducing apoptosis and autophagy in human pancreatic cancer cells. Anticancer Res 34:4685–4692

    PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Balney Rajitha & Ganji Purnachandra Nagaraju

Authors
  1. Balney Rajitha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ganji Purnachandra Nagaraju
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ganji Purnachandra Nagaraju .

Editor information

Editors and Affiliations

  1. Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia, USA

    Ganji Purnachandra Nagaraju

  2. Department of Biotechnology, Krishna University, Machilipatnam, Andhra Pradesh, India

    Pallaval Veera Bramhachari

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Rajitha, B., Nagaraju, G.P. (2017). Curcumin and Genistein Role in Regulation of STAT-3 in Pancreatic Cancer. In: Nagaraju, G., Bramhachari, P. (eds) Role of Transcription Factors in Gastrointestinal Malignancies. Springer, Singapore. https://doi.org/10.1007/978-981-10-6728-0_32

Download citation

Publish with us

Policies and ethics

Search

Navigation