Inhibitory effect of cucurbitacin E on pancreatic cancer cells growth via STAT3 signaling

  • Chunyan Sun
  • Meixia ZhangEmail author
  • Xiaolei Shan
  • Xueying Zhou
  • Jiao Yang
  • Yanli Wang
  • Jesse Li-Ling
  • Yihui Deng
Original Paper



Pancreatic cancer has been a serious disease worldwide for its high mortality. Cucurbitacin E is a member of triterpenoid family isolated from plants showing antiproliferative activity on various cancer cells. In this study, we have explored whether cucurbitacin E also has an anti-tumor effect on pancreatic cancer cells.


Human pancreatic cancer cells PANC-1 were used to explore the effect and possible mechanisms of cucurbitacin E on cell cycle progression, apoptosis and proliferation.


Cucurbitacin E has inhibited the growth of PANC-1 cells in a dose- and time-dependent manner, and has caused accumulation of cells at the G2/M phase as well as apoptosis. Western blotting also showed that cucurbitacin E treatment can inhibit STAT3 phosphorylation while upregulate p53 expression.


Our results suggested that cucurbitacin E may be an effective regimen for the chemotherapy of pancreatic cancer.


Cucurbitacin E p53 PANC-1 Pancreatic cancer STAT3 



This work has been sponsored by grants from the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (20060331) and the Natural Science Foundation of Liaoning Province, China (20082092).


  1. Al Zaid Siddiquee K, Turkson J (2008) STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res 18:254–267CrossRefPubMedGoogle Scholar
  2. Barton CM, Staddon SL, Hughes CM, Hall PA, O’Sullivan C, Kloppel G, Theis B, Russell RC, Neoptolemos J, Williamson RC (1991) Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer. Br J Cancer 64:1076–1082PubMedGoogle Scholar
  3. Bartz C, Ziske C, Wiedenmann B, Moelling K (1996) P53 tumor suppressor gene expression in pancreatic neuroendocrine tumour cells. Gut 38:403–409CrossRefPubMedGoogle Scholar
  4. Brell JM, Matin K, Evans T, Volkin RL, Kiefer GJ, Schlesselman JJ, Dranko S, Rath L, Schmotzer A, Lenzner D, Ramanathan RK (2009) Phase II study of docetaxel and gefitinib as second-line therapy in gemcitabine pretreated patients with advanced pancreatic cancer. Oncology 76:270–274CrossRefPubMedGoogle Scholar
  5. Butz J, Wickstrom E, Edwards J (2003) Characterization of mutation and loss of heterozygosity of 53 and K-ras-2 in pancreatic cancer cell lines by immobilized polymerase chain reaction. BMC Biotechnol 3:11CrossRefPubMedGoogle Scholar
  6. Duan Z, Foster R, Bell DA, Mahoney J, Wolak K, Vaidya A, Hampel C, Lee H, Seiden MV (2006) Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin Cancer Res 12:5055–5063CrossRefPubMedGoogle Scholar
  7. Duncan MD, Duncan KL (1997) Cucurbitacin E targets proliferating endothelia. J Surg Res 69:55–60CrossRefPubMedGoogle Scholar
  8. Germain D, Frank DA (2007) Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin Cancer Res 13:5665–5669CrossRefPubMedGoogle Scholar
  9. Jayaprakasam B, Seeram NP, Nair MG (2003) Anticancer and antiinflammatory activities of cucurbitacins from Cucurbita andreana. Cancer Lett 189:11–16CrossRefPubMedGoogle Scholar
  10. Kalthoff H, Schmiegel W, Roeder C, Kasche D, Schmidt A, Lauer G, Thiele H-G, Honold G, Pantel K, Riethmuller G, Scherer E, Maurer J, Maacke H, Deppert W (1993) P53 and K-RAS alterations in pancreatic epithelial cell lesions. Oncogene 8:289–298PubMedGoogle Scholar
  11. Kang SP, Saif MW (2008) Pharmacogenomics and pancreatic cancer treatment. Optimizing current therapy and individualizing future therapy. J Pancreas (Online) 9:251–266Google Scholar
  12. Kullmann F, Hollerbach S, Dollinger MM, Harder J, Fuchs M, Messmann H, Trojan J, Gabele E, Hinke A, Hollerbach C, Endlicher E (2009) Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study. Br J Cancer 100:1032–1036CrossRefPubMedGoogle Scholar
  13. Lau ST, Lin ZX, Liao Y, Zhao M, Cheng CH, Leung PS (2009) Bruceine D induces apoptosis in pancreatic adenocarcinoma cell line PANC-1 through the activation of p38-mitogen activated protein kinase. Cancer Lett 281:42–52CrossRefPubMedGoogle Scholar
  14. Lee GW, Kim HJ, Ju JH, Kim SH, Kim HG, Kim TH, Kim HJ, Jeong CY, Kang JH (2009) Phase II trial of S-1 in combination with gemcitabine for chemo-naive patients with locally advanced or metastatic pancreatic cancer. Cancer Chemother Pharmacol 64:707–713CrossRefPubMedGoogle Scholar
  15. Lewis HD, Winter A, Murphy TF, Tripathi S, Pandey VN, Barton BE (2008) STAT3 inhibition in prostate and pancreatic cancer lines by STAT3 binding sequence oligonucleotides: differential activity between 5′ and 3′ ends. Mol Cancer Ther 7:1543–1550CrossRefPubMedGoogle Scholar
  16. Li J, Orr B, White K, Belogortseva N, Niles R, Boskovic G, Nguyen H, Dykes A, Park M (2009) Chmp 1A is a mediator of the anti-proliferative effects of all-trans retinoic acid in human pancreatic cancer cells. Mol Cancer 8:7CrossRefPubMedGoogle Scholar
  17. Liu T, Zhang M, Zhang H, Sun C, Deng Y (2008) Inhibitory effects of cucurbitacin B on laryngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol 265:1225–1232CrossRefPubMedGoogle Scholar
  18. Momma K, Masuzawa Y, Nakai N, Chujo M, Murakami A, Kioka N, Kiyama Y, Akita T, Nagao M (2008) Direct interaction of cucurbitacin E isolated from Alsomitra macrocarpa to actin filament. Cytotechnology 56:33–39CrossRefPubMedGoogle Scholar
  19. Moses SA, Ali MA, Zuohe S, Du-Cuny L, Zhou LL, Lemos R, Ihle N, Skillman AG, Zhang S, Mash EA, Powis G, Meuillet EJ (2009) In vitro and in vivo activity of novel small-molecule inhibitors targeting the pleckstrin homology domain of protein kinase B/AKT. Cancer Res 69:5073–5081CrossRefPubMedGoogle Scholar
  20. Nieto J, Grossbard ML, Kozuch P (2008) Metastatic pancreatic cancer 2008: is the glass less empty? Oncologist 13:562–576CrossRefPubMedGoogle Scholar
  21. Niu G, Wright KL, Ma Y, Wright GM, Huang M, Irby R, Briggs J, Karras J, Cress WD, Pardoll D, Jove R, Chen J, Yu H (2005) Role of Stat3 in regulating p53 expression and function. Mol Cell Biol 25:7432–7440CrossRefPubMedGoogle Scholar
  22. Pan X, Arumugam T, Yamamoto T, Levin PA, Ramachandran V, Ji B, Lopez-Berestein G, Vivas-Mejia PE, Sood AK, McConkey DJ, Logsdon CD (2008) Nuclear factor-kappaB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells. Clin Cancer Res 14:8143–8151CrossRefPubMedGoogle Scholar
  23. Qiu Z, Huang C, Sun J, Qiu W, Zhang J, Li H, Jiang T, Huang K, Cao J (2007) RNA interference-mediated signal transducers and activators of transcription 3 gene silencing inhibits invasion and metastasis of human pancreatic cancer cells. Cancer Sci 98:1099–1106CrossRefPubMedGoogle Scholar
  24. Rosa DD, Ismael G, Lago LD, Awada A (2008) Molecular-targeted therapies: lessons from years of clinical development. Cancer Treat Rev 34:61–80CrossRefPubMedGoogle Scholar
  25. Ruggeri B, Zhang Z-Y, Caamono J, DiRado M, Flynn SD, Klein-Szanto AJP (1992) Human pancreatic carcinomas and cell lines reveal frequent and multiple alterations in the p53 and Rb-1 tumor-suppressor genes. Oncogene 7:1503–1511PubMedGoogle Scholar
  26. 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 101:176–193CrossRefPubMedGoogle Scholar
  27. Saif MW, Tytler E, Lansigan F, Brown DM, Husband AJ (2009) Flavonoids, phenoxodiol, and a novel agent, triphendiol, for the treatment of pancreaticobiliary cancers. Expert Opin Investig Drugs 18:469–479CrossRefPubMedGoogle Scholar
  28. Sun J, Blaskovich MA, Jove R, Livingston SK, Coppola D, Sebti SM (2005) Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity. Oncogene 24:3236–3245CrossRefPubMedGoogle Scholar
  29. Sun X, Zhang J, Wang L, Tian Z (2008) Growth inhibition of human hepatocellular carcinoma cells by blocking STAT3 activation with decoy-ODN. Cancer Lett 262:201–213CrossRefPubMedGoogle Scholar
  30. Tannin-Spitz T, Grossman S, Dovrat S, Gottlieb HE, Bergman M (2007) Growth inhibitory activity of cucurbitacin glucosides isolated from Citrullus colocynthis on human breast cancer cells. Biochem Pharmacol 73:56–67CrossRefPubMedGoogle Scholar
  31. Wakimoto N, Yin D, O’Kelly J, Haritunians T, Karlan B, Said J, Xing H, Koeffler HP (2008) Cucurbitacin B has a potent antiproliferative effect on breast cancer cells in vitro and in vivo. Cancer Sci 99:1793–1797CrossRefPubMedGoogle Scholar
  32. Wang ML, Foo KF (2009) Adjuvant chemoradiotherapy for high-risk pancreatic cancer. Singap Med J 50:43–48Google Scholar
  33. Yin D, Wakimoto N, Xing H, Lu D, Huynh T, Wang X, Black KL, Koeffler HP (2008) Cucurbitacin B markedly inhibits growth and rapidly affects the cytoskeleton in glioblastoma multiforme. Int J Cancer 123:1364–1375CrossRefPubMedGoogle Scholar
  34. Zhang M, Zhang H, Sun C, Shan X, Yang X, Li-Ling J, Deng Y (2009) Targeted constitutive activation of signal transducer and activator of transcription 3 in human hepatocellular carcinoma cells by cucurbitacin B. Cancer Chemother Pharmacol 63:635–642CrossRefPubMedGoogle Scholar
  35. Zhao S, Venkatasubbarao K, Lazor JW, Sperry J, Jin C, Cao L, Freeman JW (2008) Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Res 68:4221–4228CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Chunyan Sun
    • 1
  • Meixia Zhang
    • 1
    Email author
  • Xiaolei Shan
    • 1
  • Xueying Zhou
    • 1
  • Jiao Yang
    • 1
  • Yanli Wang
    • 1
  • Jesse Li-Ling
    • 2
  • Yihui Deng
    • 3
  1. 1.Department of Clinical PharmacologyChina Medical UniversityShenyangChina
  2. 2.Department of Medical GeneticsChina Medical UniversityShenyangChina
  3. 3.Department of PharmacyShenyang Pharmaceutical UniversityShenyangChina

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