Pancreatic Cancer: Role of STAT-3 and Intervention of STAT-3 by Genistein

Chapter

Abstract

Pancreatic cancer (PC) is a cancer that is initiated in the pancreas and spreads rapidly to other organs. Pancreatic cancer is the third most leading cause of cancer-related deaths in the United States (US) and is often regarded as one of the deadliest cancers with 95% mortality within 5 years of detection, which is the highest compared to the rest of any cancer-related deaths. Pancreatic cancer is tough to diagnose at early stages, and by the time the patient is hospitalized and detected with pancreatic cancer, it is already in advanced stages. Apart from surgical procedures, inhibition of many key proteins that are tumorigenic pathways has been tested in several model systems including mouse and are further corroborated in various clinical studies. Included in that group of several tumorigenic proteins is the signal transducer and activator of transcription 3 protein, namely, STAT-3. STATs were identified in the year 1994 that traffic signals from the activated cell surface receptors internally to the nucleus and act as potent transcription factor (TF) that regulates several key aspects of intracellular functioning, namely, cell proliferation, cell differentiation, apoptotic cell death, and angiogenesis. In normal cells, STATs are in non-phosphorylated, inactive form, but upon external stimuli, they are phosphorylated and activated that leads to translocation to the nucleus and act as transcription factors. In the STAT family, STAT-3 functions are most important as STAT-3 knockout are lethal and mice are reported to die at day 7.5. STAT-3 inhibition by RNAi or chemical compound in vivo in model systems such as mice led to a block in ductal adenocarcinomas and PanIN formation. Mouse models expressing endogenous mutant Kras mutation, STAT-3 found to phosphorylated and significantly activated. Due to STAT-3 established role in angiogenesis, several chemical and natural compounds have been developed and tested over the last two decades. STAT-3 inhibitors such as nexrutine, crizotinib, and miR-216a overexpression have shown to inhibit pancreatic cancer growth by reducing the STAT-3 activity levels. Chemical compounds such as thiosemicarbazone treatment in vitro and in vivo (model systems) inhibited interleukin-6 (IL-6)-induced activation of STAT-3 by the decrease in phosphorylation at Tyr705. Metformin along with aspirin doses significantly reduced the phosphorylation of STAT-3 and mechanistic target of rapamycin (mTOR). Apart from several chemicals mentioned above, there are various natural products such as genistein derivatives used as STAT-3 inhibitors. Genistein was used and tested in treatment of pancreatic, breast, and prostate cancer (PC). Genistein is shown to prevent p-STAT-3 binding to DNA in a concentration-dependent manner. Pretreatment of human pancreatic cancer cell lines such as COLO 357 and L3.6pl, by genistein for 24 h followed by gemcitabine, resulted in inhibition of growth up to 80% compared to only 30% in gemcitabine alone condition. In 2016, promising results were published from the clinical study conducted at Karolinska where patients who received genistein lived 6 months longer than their counterparts. A crystalline formulation of genistein, namely, AXP107-11, has been shown to have improved physiochemical properties and oral bioavailability in comparison to other universal forms of genistein. Pancreatic cancer (PC) patients treated with AXP107-11 along with gemcitabine resulted in improved survival. Forty-four percent of the total 16 patients in the study survived longer than 6 months, and half of them even survived longer than a year.

References

  1. 1.
    Ango PY, Kapche DW, Fotso GW, Fozing CD, Yeboah EM, Mapitse R, Demirtas I, Ngadjui BT, Yeboah SO (2016) Thonningiiflavanonol A and thonningiiflavanonol B, two novel flavonoids, and other constituents of Ficus thonningii Blume (Moraceae). Z Naturforsch C J Biosci 71(3–4):65–71.  https://doi.org/10.1515/znc-2015-0147 Google Scholar
  2. 2.
    Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363(9414):1049–1057.  https://doi.org/10.1016/S0140-6736(04)15841-8 PubMedCrossRefGoogle Scholar
  3. 3.
    Hidalgo M (2010) Pancreatic cancer. N Engl J Med 362(17):1605–1617.  https://doi.org/10.1056/NEJMra0901557 PubMedCrossRefGoogle Scholar
  4. 4.
    Ferlay J, Partensky C, Bray F (2016) More deaths from pancreatic cancer than breast cancer in the EU by 2017. Acta Oncol 55(9–10):1158–1160.  https://doi.org/10.1080/0284186X.2016.1197419 PubMedCrossRefGoogle Scholar
  5. 5.
    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66(1):7–30.  https://doi.org/10.3322/caac.21332 PubMedCrossRefGoogle Scholar
  6. 6.
    Vincent A, Herman J, Schulick R, Hruban RH, Goggins M (2011) Pancreatic cancer. Lancet 378(9791):607–620.  https://doi.org/10.1016/S0140-6736(10)62307-0 PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Torre LA, Sauer AM, Chen MS Jr, Kagawa-Singer M, Jemal A, Siegel RL (2016) Cancer statistics for Asian Americans, Native Hawaiians, and Pacific Islanders, 2016: converging incidence in males and females. CA Cancer J Clin 66(3):182–202.  https://doi.org/10.3322/caac.21335 PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Steele CW, Kaur Gill NA, Jamieson NB, Carter CR (2016) Targeting inflammation in pancreatic cancer: clinical translation. World J Gastrointest Oncol 8(4):380–388.  https://doi.org/10.4251/wjgo.v8.i4.380 PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264(5164):1415–1421PubMedCrossRefGoogle Scholar
  10. 10.
    Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T, Akira S (1997) Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci U S A 94(8):3801–3804PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Brahmer JR, Lee JW, Traynor AM, Hidalgo MM, Kolesar JM, Siegfried JM, Guaglianone PP, Patel JD, Keppen MD, Schiller JH (2014) Dosing to rash: a phase II trial of the first-line erlotinib for patients with advanced non-small-cell lung cancer an Eastern Cooperative Oncology Group Study (E3503). Eur J Cancer 50(2):302–308.  https://doi.org/10.1016/j.ejca.2013.10.006 PubMedCrossRefGoogle Scholar
  12. 12.
    Ma J, Zhang T, Novotny-Diermayr V, Tan AL, Cao X (2003) A novel sequence in the coiled-coil domain of Stat3 essential for its nuclear translocation. J Biol Chem 278(31):29252–29260.  https://doi.org/10.1074/jbc.M304196200 PubMedCrossRefGoogle Scholar
  13. 13.
    Frank DA (2007) STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett 251(2):199–210.  https://doi.org/10.1016/j.canlet.2006.10.017 PubMedCrossRefGoogle Scholar
  14. 14.
    Vinkemeier U (2004) Getting the message across, STAT! Design principles of a molecular signaling circuit. J Cell Biol 167(2):197–201.  https://doi.org/10.1083/jcb.200407163 PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Kanda N, Seno H, Konda Y, Marusawa H, Kanai M, Nakajima T, Kawashima T, Nanakin A, Sawabu T, Uenoyama Y, Sekikawa A, Kawada M, Suzuki K, Kayahara T, Fukui H, Sawada M, Chiba T (2004) STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene 23(28):4921–4929.  https://doi.org/10.1038/sj.onc.1207606 PubMedCrossRefGoogle Scholar
  16. 16.
    Yakata Y, Nakayama T, Yoshizaki A, Kusaba T, Inoue K, Sekine I (2007) Expression of p-STAT3 in human gastric carcinoma: significant correlation in tumour invasion and prognosis. Int J Oncol 30(2):437–442PubMedGoogle Scholar
  17. 17.
    Gong W, Wang L, Yao JC, Ajani JA, Wei D, Aldape KD, Xie K, Sawaya R, Huang S (2005) Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer. Clin Cancer Res: Off J Am Assoc Cancer Res 11(4):1386–1393.  https://doi.org/10.1158/1078-0432.CCR-04-0487 CrossRefGoogle Scholar
  18. 18.
    Zhao M, Jiang B, Gao FH (2011) Small molecule inhibitors of STAT3 for cancer therapy. Curr Med Chem 18(26):4012–4018PubMedCrossRefGoogle Scholar
  19. 19.
    Mankan AK, Greten FR (2011) Inhibiting signal transducer and activator of transcription 3: rationality and rationale design of inhibitors. Expert Opin Investig Drugs 20(9):1263–1275.  https://doi.org/10.1517/13543784.2011.601739 PubMedCrossRefGoogle Scholar
  20. 20.
    Kraskouskaya D, Duodu E, Arpin CC, Gunning PT (2013) Progress towards the development of SH2 domain inhibitors. Chem Soc Rev 42(8):3337–3370.  https://doi.org/10.1039/c3cs35449k PubMedCrossRefGoogle Scholar
  21. 21.
    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(1):39–50PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Lin L, Benson DM Jr, DeAngelis S, Bakan CE, Li PK, Li C, Lin J (2012) A small molecule, LLL12 inhibits constitutive STAT3 and IL-6-induced STAT3 signaling and exhibits potent growth suppressive activity in human multiple myeloma cells. Int J Cancer 130(6):1459–1469.  https://doi.org/10.1002/ijc.26152 PubMedCrossRefGoogle Scholar
  23. 23.
    Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR, Yip ML, Jove R, McLaughlin MM, Lawrence NJ, Sebti SM, Turkson J (2007) Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci U S A 104(18):7391–7396.  https://doi.org/10.1073/pnas.0609757104 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Xiong A, Yang Z, Shen Y, Zhou J, Shen Q (2014) Transcription factor STAT3 as a novel molecular target for cancer prevention. Cancer 6(2):926–957.  https://doi.org/10.3390/cancers6020926 CrossRefGoogle Scholar
  25. 25.
    Huang W, Dong Z, Wang F, Peng H, Liu JY, Zhang JT (2014) A small molecule compound targeting STAT3 DNA-binding domain inhibits cancer cell proliferation, migration, and invasion. ACS Chem Biol 9(5):1188–1196.  https://doi.org/10.1021/cb500071v PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Furtek SL, Backos DS, Matheson CJ, Reigan P (2016) Strategies and approaches of targeting STAT3 for cancer treatment. ACS Chem Biol 11(2):308–318.  https://doi.org/10.1021/acschembio.5b00945 PubMedCrossRefGoogle Scholar
  27. 27.
    Gaspar NJ, Li L, Kapoun AM, Medicherla S, Reddy M, Li G, O’Young G, Quon D, Henson M, Damm DL, Muiru GT, Murphy A, Higgins LS, Chakravarty S, Wong DH (2007) Inhibition of transforming growth factor beta signaling reduces pancreatic adenocarcinoma growth and invasiveness. Mol Pharmacol 72(1):152–161.  https://doi.org/10.1124/mol.106.029025 PubMedCrossRefGoogle Scholar
  28. 28.
    Goggins M, Shekher M, Turnacioglu K, Yeo CJ, Hruban RH, Kern SE (1998) Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res 58(23):5329–5332PubMedGoogle Scholar
  29. 29.
    Furukawa T, Sunamura M, Horii A (2006) Molecular mechanisms of pancreatic carcinogenesis. Cancer Sci 97(1):1–7.  https://doi.org/10.1111/j.1349-7006.2005.00134.x PubMedCrossRefGoogle Scholar
  30. 30.
    Yasutome M, Gunn J, Korc M (2005) Restoration of Smad4 in BxPC3 pancreatic cancer cells attenuates proliferation without altering angiogenesis. Clin Exp Metastasis 22(6):461–473.  https://doi.org/10.1007/s10585-005-2891-x PubMedCrossRefGoogle Scholar
  31. 31.
    Duda DG, Sunamura M, Lefter LP, Furukawa T, Yokoyama T, Yatsuoka T, Abe T, Inoue H, Motoi F, Egawa S, Matsuno S, Horii A (2003) Restoration of SMAD4 by gene therapy reverses the invasive phenotype in pancreatic adenocarcinoma cells. Oncogene 22(44):6857–6864.  https://doi.org/10.1038/sj.onc.1206751 PubMedCrossRefGoogle Scholar
  32. 32.
    Fukuda A, Wang SC, Morris JP, Folias AE, Liou A, Kim GE, Akira S, Boucher KM, Firpo MA, Mulvihill SJ, Hebrok M (2011) Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19(4):441–455.  https://doi.org/10.1016/j.ccr.2011.03.002 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Trevino JG, Summy JM, Lesslie DP, Parikh NU, Hong DS, Lee FY, Donato NJ, Abbruzzese JL, Baker CH, Gallick GE (2006) Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am J Pathol 168(3):962–972.  https://doi.org/10.2353/ajpath.2006.050570 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Macha MA, Rachagani S, Gupta S, Pai P, Ponnusamy MP, Batra SK, Jain M (2013) Guggulsterone decreases proliferation and metastatic behavior of pancreatic cancer cells by modulating JAK/STAT and Src/FAK signaling. Cancer Lett 341(2):166–177.  https://doi.org/10.1016/j.canlet.2013.07.037 PubMedCrossRefGoogle Scholar
  35. 35.
    Wang S, Chen X, Tang M (2014) MicroRNA-216a inhibits pancreatic cancer by directly targeting Janus kinase 2. Oncol Rep 32(6):2824–2830.  https://doi.org/10.3892/or.2014.3478 PubMedCrossRefGoogle Scholar
  36. 36.
    Yan HH, Jung KH, Son MK, Fang Z, Kim SJ, Ryu YL, Kim J, Kim MH, Hong SS (2014) Crizotinib exhibits antitumor activity by targeting ALK signaling not c-MET in pancreatic cancer. Oncotarget 5(19):9150–9168.  10.18632/oncotarget.2363 PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Gong J, Xie J, Bedolla R, Rivas P, Chakravarthy D, Freeman JW, Reddick R, Kopetz S, Peterson A, Wang H, Fischer SM, Kumar AP (2014) Combined targeting of STAT3/NF-kappaB/COX-2/EP4 for effective management of pancreatic cancer. Clin Cancer Res: Off J Am Assoc Cancer Res 20(5):1259–1273.  https://doi.org/10.1158/1078-0432.CCR-13-1664 CrossRefGoogle Scholar
  38. 38.
    Lui GY, Kovacevic Z, VMenezes S, Kalinowski DS, Merlot AM, Sahni S, Richardson DR (2015) Novel thiosemicarbazones regulate the signal transducer and activator of transcription 3 (STAT3) pathway: inhibition of constitutive and interleukin 6-induced activation by iron depletion. Mol Pharmacol 87(3):543–560.  https://doi.org/10.1124/mol.114.096529 PubMedCrossRefGoogle Scholar
  39. 39.
    Yue W, Zheng X, Lin Y, Yang CS, Xu Q, Carpizo D, Huang H, DiPaola RS, Tan XL (2015) Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2. Oncotarget 6(25):21208–21224.  10.18632/oncotarget.4126 PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Sarkar FH, Li Y (2003) Soy isoflavones and cancer prevention. Cancer Investig 21(5):744–757CrossRefGoogle Scholar
  41. 41.
    Park OJ (2004) Comparison of estrogen and genistein in their antigenotoxic effects, apoptosis and signal transduction protein expression patterns. Biofactors 21(1–4):379–382PubMedCrossRefGoogle Scholar
  42. 42.
    Park OJ, Surh YJ (2004) Chemopreventive potential of epigallocatechin gallate and genistein: evidence from epidemiological and laboratory studies. Toxicol Lett 150(1):43–56.  https://doi.org/10.1016/j.toxlet.2003.06.001 PubMedCrossRefGoogle Scholar
  43. 43.
    Setchell KD (1998) Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr 68(6 Suppl):1333S–1346SPubMedCrossRefGoogle Scholar
  44. 44.
    Adlercreutz H (1995) Phytoestrogens: epidemiology and a possible role in cancer protection. Environ Health Perspect 103(Suppl 7):103–112PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Wahala K, Hase T, Adlercreutz H (1995) Synthesis and labeling of isoflavone phytoestrogens, including daidzein and genistein. Proc Soc Exp Biol Med 208(1):27–32PubMedCrossRefGoogle Scholar
  46. 46.
    Adlercreutz H (1990) Western diet and Western diseases: some hormonal and biochemical mechanisms and associations. Scand J Clin Lab Investig Suppl 201:3–23CrossRefGoogle Scholar
  47. 47.
    Yu H, Harris RE, Gao YT, Gao R, Wynder EL (1991) Comparative epidemiology of cancers of the colon, rectum, prostate and breast in Shanghai, China versus the United States. Int J Epidemiol 20(1):76–81PubMedCrossRefGoogle Scholar
  48. 48.
    Rose DP, Boyar AP, Wynder EL (1986) International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption. Cancer 58(11):2363–2371PubMedCrossRefGoogle Scholar
  49. 49.
    Adlercreutz CH, Goldin BR, Gorbach SL, Hockerstedt KA, Watanabe S, Hamalainen EK, Markkanen MH, Makela TH, Wahala KT, Adlercreutz T (1995) Soybean phytoestrogen intake and cancer risk. J Nutr 125(3 Suppl):757S–770SPubMedGoogle Scholar
  50. 50.
    Muir IM, Ellis IO, Bell J, Robins RA (1987) NCRC-11 immunoperoxidase staining patterns in breast cancer: interpretive and technical reproducibility. Histopathology 11(11):1208–1210PubMedGoogle Scholar
  51. 51.
    Sarkar FH, Li Y (2004) The role of isoflavones in cancer chemoprevention. Front Biosci: J Virtual Libr 9:2714–2724CrossRefGoogle Scholar
  52. 52.
    Davis JN, Kucuk O, Sarkar FH (1999) Genistein inhibits NF-kappa B activation in prostate cancer cells. Nutr Cancer 35(2):167–174.  https://doi.org/10.1207/S15327914NC352_11 PubMedCrossRefGoogle Scholar
  53. 53.
    Raffoul JJ, Wang Y, Kucuk O, Forman JD, Sarkar FH, Hillman GG (2006) Genistein inhibits radiation-induced activation of NF-kappaB in prostate cancer cells promoting apoptosis and G2/M cell cycle arrest. BMC Cancer 6:107.  https://doi.org/10.1186/1471-2407-6-107 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Li HC, Zhang GY (2003) Inhibitory effect of genistein on activation of STAT3 induced by brain ischemia/reperfusion in rat hippocampus. Acta Pharmacol Sin 24(11):1131–1136PubMedGoogle Scholar
  55. 55.
    Mohammad RM, Banerjee S, Li Y, Aboukameel A, Kucuk O, Sarkar FH (2006) Cisplatin-induced antitumor activity is potentiated by the soy isoflavone genistein in BxPC-3 pancreatic tumor xenografts. Cancer 106(6):1260–1268.  https://doi.org/10.1002/cncr.21731 PubMedCrossRefGoogle Scholar
  56. 56.
    Lohr JM, Karimi M, Omazic B, Kartalis N, Verbeke CS, Berkenstam A, Frodin JE (2016) A phase I dose escalation trial of AXP107-11, a novel multi-component crystalline form of genistein, in combination with gemcitabine in chemotherapy-naive patients with unresectable pancreatic cancer. Pancreatology 16(4):640–645.  https://doi.org/10.1016/j.pan.2016.05.002 PubMedCrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd 2017

Authors and Affiliations

  1. 1.Department of NeurologyEmory UniversityAtlantaUSA
  2. 2.Department of GastroenterolgyCedar-Sinai Medical CenterLos AngelesUSA

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