Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Al Zaid Siddiquee K, Turkson J (2008) STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res 18:254–267

    Article  CAS  PubMed  Google Scholar 

  • 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 64:1076–1082

    CAS  PubMed  Google Scholar 

  • Bartz C, Ziske C, Wiedenmann B, Moelling K (1996) P53 tumor suppressor gene expression in pancreatic neuroendocrine tumour cells. Gut 38:403–409

    Article  CAS  PubMed  Google Scholar 

  • 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 76:270–274

    Article  CAS  PubMed  Google Scholar 

  • 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 3:11

    Article  PubMed  Google Scholar 

  • 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 12:5055–5063

    Article  CAS  PubMed  Google Scholar 

  • Duncan MD, Duncan KL (1997) Cucurbitacin E targets proliferating endothelia. J Surg Res 69:55–60

    Article  CAS  PubMed  Google Scholar 

  • 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 13:5665–5669

    Article  CAS  PubMed  Google Scholar 

  • Jayaprakasam B, Seeram NP, Nair MG (2003) Anticancer and antiinflammatory activities of cucurbitacins from Cucurbita andreana. Cancer Lett 189:11–16

    Article  CAS  PubMed  Google Scholar 

  • 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 8:289–298

    CAS  PubMed  Google Scholar 

  • Kang SP, Saif MW (2008) Pharmacogenomics and pancreatic cancer treatment. Optimizing current therapy and individualizing future therapy. J Pancreas (Online) 9:251–266

    Google Scholar 

  • 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 100:1032–1036

    Article  CAS  PubMed  Google Scholar 

  • 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 281:42–52

    Article  CAS  PubMed  Google Scholar 

  • 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 64:707–713

    Article  CAS  PubMed  Google Scholar 

  • 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 7:1543–1550

    Article  CAS  PubMed  Google Scholar 

  • 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 8:7

    Article  PubMed  Google Scholar 

  • Liu T, Zhang M, Zhang H, Sun C, Deng Y (2008) Inhibitory effects of cucurbitacin B on laryngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol 265:1225–1232

    Article  PubMed  Google Scholar 

  • 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 56:33–39

    Article  PubMed  Google Scholar 

  • 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 69:5073–5081

    Article  CAS  PubMed  Google Scholar 

  • Nieto J, Grossbard ML, Kozuch P (2008) Metastatic pancreatic cancer 2008: is the glass less empty? Oncologist 13:562–576

    Article  CAS  PubMed  Google Scholar 

  • 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 25:7432–7440

    Article  CAS  PubMed  Google Scholar 

  • 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 14:8143–8151

    Article  CAS  PubMed  Google Scholar 

  • 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 98:1099–1106

    Article  CAS  PubMed  Google Scholar 

  • Rosa DD, Ismael G, Lago LD, Awada A (2008) Molecular-targeted therapies: lessons from years of clinical development. Cancer Treat Rev 34:61–80

    Article  CAS  PubMed  Google Scholar 

  • 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 7:1503–1511

    CAS  PubMed  Google Scholar 

  • 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 101:176–193

    Article  CAS  PubMed  Google Scholar 

  • 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 18:469–479

    Article  CAS  PubMed  Google Scholar 

  • 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 24:3236–3245

    Article  CAS  PubMed  Google Scholar 

  • 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 262:201–213

    Article  CAS  PubMed  Google Scholar 

  • 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 73:56–67

    Article  CAS  PubMed  Google Scholar 

  • 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 99:1793–1797

    Article  CAS  PubMed  Google Scholar 

  • Wang ML, Foo KF (2009) Adjuvant chemoradiotherapy for high-risk pancreatic cancer. Singap Med J 50:43–48

    CAS  Google Scholar 

  • 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 123:1364–1375

    Article  CAS  PubMed  Google Scholar 

  • 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 63:635–642

    Article  CAS  PubMed  Google Scholar 

  • 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 68:4221–4228

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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).

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, China Medical University, 92 Bei’er Road, 110001, Shenyang, China

    Chunyan Sun, Meixia Zhang, Xiaolei Shan, Xueying Zhou, Jiao Yang & Yanli Wang

  2. Department of Medical Genetics, China Medical University, 110001, Shenyang, China

    Jesse Li-Ling

  3. Department of Pharmacy, Shenyang Pharmaceutical University, 110015, Shenyang, China

    Yihui Deng

Authors
  1. Chunyan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meixia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaolei Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xueying Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yanli Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jesse Li-Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yihui Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meixia Zhang.

Additional information

C. Sun and M. Zhang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sun, C., Zhang, M., Shan, X. et al. Inhibitory effect of cucurbitacin E on pancreatic cancer cells growth via STAT3 signaling. J Cancer Res Clin Oncol 136, 603–610 (2010). https://doi.org/10.1007/s00432-009-0698-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-009-0698-x

Keywords

Search

Navigation