Hypoxia-Inducible Factor (HIF)-1α and Its Regulation in Pancreatic Cancer

  • Ganji Purnachandra NagarajuEmail author
  • Subasini PattnaikEmail author


Pancreatic malignancy is a highly metastatic disease with a poor prognosis and extremely low overall survival rates. Despite recent advancements in the traditional chemopreventive approaches for pancreatic cancer (PC), there has been very little improvement in the overall survival rates for patients (Guilford JM, Pezzuto JM, Expert Opin Investig Drugs 17:1341–1352, 2008). Therefore, novel phytochemicals such as curcumin and genistein have emerged as promising targets in developing treatment options for patients with PC. Curcumin is a natural compound found in turmeric (Kunnumakkara AB, Guha S, Krishnan S et al, Cancer Res 67:3853–3861, 2007), and genistein is an isoflavone found in soybeans (Banerjee S, Zhang Y, Ali S et al, Cancer Res 65:9064–9072, 2005). Both compounds are known to possess outstanding anti-inflammatory, antioxidant, and anticancer properties.


Hypoxia-inducible factor 1 Curcumin Pancreatic cancer 


  1. 1.
    Akakura N, Kobayashi M, Horiuchi I et al (2001) Constitutive expression of hypoxia-inducible factor-1α renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res 61:6548–6554PubMedGoogle Scholar
  2. 2.
    Banerjee S, Zhang Y, Ali S et al (2005) Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res 65:9064–9072CrossRefPubMedGoogle Scholar
  3. 3.
    Bhattacharya S, Michels CL, Leung M-K et al (1999) Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev 13:64–75CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bilton RL, Booker GW (2003) The subtle side to hypoxia inducible factor (HIFα) regulation. Eur J Biochem 270:791–798CrossRefPubMedGoogle Scholar
  5. 5.
    Brusselmans K, Bono F, Maxwell P et al (2001) Hypoxia-inducible factor-2α (HIF-2α) is involved in the apoptotic response to hypoglycemia but not to hypoxia. J Biol Chem 276:39192–39196CrossRefPubMedGoogle Scholar
  6. 6.
    Büchler P, Reber HA, Büchler MW et al (2004) Antiangiogenic activity of genistein in pancreatic carcinoma cells is mediated by the inhibition of hypoxia-inducible factor-1 and the down-regulation of VEGF gene expression. Cancer 100:201–210CrossRefPubMedGoogle Scholar
  7. 7.
    Bussink J, Van Der Kogel AJ, Kaanders JH (2008) Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol 9:288–296CrossRefPubMedGoogle Scholar
  8. 8.
    Conrad PW, Freeman TL, Beitner-Johnson D et al (1999) EPAS1 trans-activation during hypoxia requires p42/p44 MAPK. J Biol Chem 274:33709–33713CrossRefPubMedGoogle Scholar
  9. 9.
    D’ignazio L, Batie M, Rocha S (2017) Hypoxia and inflammation in cancer, focus on HIF and NF-κB. Biomedicine 5:21CrossRefGoogle Scholar
  10. 10.
    Ema M, Hirota K, Mimura J et al (1999) Molecular mechanisms of transcription activation by HLF and HIF1α in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. EMBO J 18:1905–1914CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ema M, Taya S, Yokotani N et al (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci 94:4273–4278CrossRefPubMedGoogle Scholar
  12. 12.
    Feldser D, Agani F, Iyer NV et al (1999) Reciprocal positive regulation of hypoxia-inducible factor 1α and insulin-like growth factor 2. Cancer Res 59:3915–3918PubMedGoogle Scholar
  13. 13.
    Flamme I, Fröhlich T, Von Reutern M et al (1997) HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1< i> α</i> and developmentally expressed in blood vessels. Mech Dev 63:51–60CrossRefPubMedGoogle Scholar
  14. 14.
    Fukuda R, Hirota K, Fan F et al (2002) Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem 277:38205–38211CrossRefPubMedGoogle Scholar
  15. 15.
    Gingras A-C, Raught B, Sonenberg N (2001) Regulation of translation initiation by FRAP/mTOR. Genes Dev 15:807–826CrossRefPubMedGoogle Scholar
  16. 16.
    Görlach A, Diebold I, Schini-Kerth V et al (2001) Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells role of the p22phox-containing NADPH oxidase. Circ Res 89:47–54CrossRefPubMedGoogle Scholar
  17. 17.
    Greijer A, Van Der Wall E (2004) The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J Clin Pathol 57:1009–1014CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Guilford JM, Pezzuto JM (2008) Natural products as inhibitors of carcinogenesis. Expert Opin Investig Drugs 17:1341–1352CrossRefPubMedGoogle Scholar
  19. 19.
    Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47CrossRefPubMedGoogle Scholar
  20. 20.
    Hellwig-Bürgel T, Rutkowski K, Metzen E et al (1999) Interleukin-1β and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1. Blood 94:1561–1567PubMedGoogle Scholar
  21. 21.
    Hewitson KS, Mcneill LA, Riordan MV et al (2002) Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem 277:26351–26355CrossRefGoogle Scholar
  22. 22.
    Huang LE, Arany Z, Livingston DM et al (1996) Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its α subunit. J Biol Chem 271:32253–32259CrossRefPubMedGoogle Scholar
  23. 23.
    Huang LE, Bunn HF (2003) Hypoxia-inducible factor and its biomedical relevance. J Biol Chem 278:19575–19578CrossRefPubMedGoogle Scholar
  24. 24.
    Ikushima H, Miyazono K (2010) TGFβ signalling: a complex web in cancer progression. Nat Rev Cancer 10:415–424CrossRefPubMedGoogle Scholar
  25. 25.
    Ji Q, Hao X, Zhang M et al (2009) MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 4:e6816CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Jiang B-H, Agani F, Passaniti A et al (1997a) 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 57:5328–5335PubMedGoogle Scholar
  27. 27.
    Jiang B-H, Zheng JZ, Leung SW et al (1997b) Transactivation and inhibitory domains of hypoxia-inducible factor 1α modulation of transcriptional activity by oxygen tension. J Biol Chem 272:19253–19260CrossRefPubMedGoogle Scholar
  28. 28.
    Jutooru I, Chadalapaka G, Lei P et al (2010) Inhibition of NFκB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation. J Biol Chem 285:25332–25344CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kunnumakkara AB, Guha S, Krishnan S et al (2007) Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-κB–regulated gene products. Cancer Res 67:3853–3861CrossRefPubMedGoogle Scholar
  30. 30.
    Lando D, Peet DJ, Gorman JJ et al (2002a) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16:1466–1471CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lando D, Peet DJ, Whelan DA et al (2002b) Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science 295:858–861CrossRefPubMedGoogle Scholar
  32. 32.
    Laughner E, Taghavi P, Chiles K et al (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 21:3995–4004CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Li Y, Vandenboom TG, Wang Z et al (2010) miR-146a suppresses invasion of pancreatic cancer cells. Cancer Res 70:1486–1495CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Liao D, Johnson RS (2007) Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev 26:281–290CrossRefPubMedGoogle Scholar
  35. 35.
    Masson N, Ratcliffe PJ (2003) HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O2 levels. J Cell Sci 116:3041–3049CrossRefPubMedGoogle Scholar
  36. 36.
    Mazure NM, Chen EY, Laderoute KR et al (1997) Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood 90:3322–3331PubMedGoogle Scholar
  37. 37.
    Minet E, Arnould T, Michel G et al (2000) ERK activation upon hypoxia: involvement in HIF-1 activation. FEBS Lett 468:53–58CrossRefPubMedGoogle Scholar
  38. 38.
    Mole D, Maxwell P, Pugh C et al (2001) Regulation of HIF by the von Hippel-Lindau tumour suppressor: implications for cellular oxygen sensing. IUBMB Life 52:43–47CrossRefPubMedGoogle Scholar
  39. 39.
    Pugh CW, O’rourke JF, Nagao M et al (1997) Activation of hypoxia-inducible factor-1; definition of regulatory domains within the α subunit. J Biol Chem 272:11205–11214CrossRefPubMedGoogle Scholar
  40. 40.
    Richard DE, Berra E, Gothié E et al (1999) p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1α (HIF-1α) and enhance the transcriptional activity of HIF-1. J Biol Chem 274:32631–32637CrossRefPubMedGoogle Scholar
  41. 41.
    Saha S, Sadhukhan P, Sil PC (2014) Genistein: a phytoestrogen with multifaceted therapeutic properties. Mini-Rev Med Chem 14:920–940CrossRefGoogle Scholar
  42. 42.
    Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732CrossRefGoogle Scholar
  43. 43.
    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30CrossRefGoogle Scholar
  44. 44.
    Sodhi A, Montaner S, Patel V et al (2000) The Kaposi’s sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1α. Cancer Res 60:4873–4880PubMedGoogle Scholar
  45. 45.
    Stiehl DP, Jelkmann W, Wenger RH et al (2002) Normoxic induction of the hypoxia-inducible factor 1α by insulin and interleukin-1β involves the phosphatidylinositol 3-kinase pathway. FEBS Lett 512:157–162CrossRefPubMedGoogle Scholar
  46. 46.
    Tacchini L, Dansi P, Matteucci E et al (2001) Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells. Carcinogenesis 22:1363–1371CrossRefPubMedGoogle Scholar
  47. 47.
    Thornton R, Lane P, Borghaei R et al (2000) Interleukin 1 induces hypoxia-inducible factor 1 in human gingival and synovial fibroblasts. Biochem J 350:307–312CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Tian H, Mcknight SL, Russell DW (1997) Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11:72–82CrossRefGoogle Scholar
  49. 49.
    Treins C, Giorgetti-Peraldi S, Murdaca J et al (2002) Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J Biol Chem 277:27975–27981CrossRefPubMedGoogle Scholar
  50. 50.
    Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nat Rev Cancer 2:489–501CrossRefPubMedGoogle Scholar
  51. 51.
    Wang GL, Jiang B-H, Rue EA et al (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci 92:5510–5514CrossRefPubMedGoogle Scholar
  52. 52.
    Wang GL, Semenza GL (1995) Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270:1230–1237CrossRefPubMedGoogle Scholar
  53. 53.
    Wiesener M, Turley H, Allen W et al (1998) Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1α. Blood 92:2260–2268PubMedGoogle Scholar
  54. 54.
    Wiesener MS, Jürgensen JS, Rosenberger C et al (2003) Widespread hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J 17:271–273CrossRefGoogle Scholar
  55. 55.
    Xia J, Duan Q, Ahmad A et al (2012) Genistein inhibits cell growth and induces apoptosis through up-regulation of miR-34a in pancreatic cancer cells. Curr Drug Targets 13:1750–1756CrossRefPubMedGoogle Scholar
  56. 56.
    Yu F, White SB, Zhao Q et al (2001) HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci 98:9630–9635CrossRefPubMedGoogle Scholar
  57. 57.
    Yuan Y, Hilliard G, Ferguson T et al (2003) Cobalt inhibits the interaction between hypoxia-inducible factor-α and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-α. J Biol Chem 278:15911–15916CrossRefPubMedGoogle Scholar
  58. 58.
    Zagórska A, Dulak J (2004) HIF-1: the knowns and unknowns of hypoxia sensing. Acta Biochim Pol 51:563–585PubMedGoogle Scholar
  59. 59.
    Zelzer E, Levy Y, Kahana C et al (1998) Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1α/ARNT. EMBO J 17:5085–5094CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Zhong H, Chiles K, Feldser D et al (2000a) 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 60:1541–1545PubMedGoogle Scholar
  61. 61.
    Zundel W, Schindler C, Haas-Kogan D et al (2000) Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 14:391–396PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd 2017

Authors and Affiliations

  1. 1.Department of Hematology and Medical OncologyEmory UniversityAtlantaUSA
  2. 2.Department of Zoology and Department of BiotechnologyBerhampur UniversityBerhampurIndia

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