Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of Notch3 enhances sensitivity to gemcitabine in pancreatic cancer through an inactivation of PI3K/Akt-dependent pathway

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Notch3 is one of the four Notch receptors identified in mammal, but its role in human pancreatic cancer remains poorly characterized. In this study, we sought to determine the effect of suppressing Notch3 expression on the chemosensitivity to gemcitabine in human pancreatic cancer cell lines BxPC-3 and PANC-1. RNA interference was used to suppress Notch3 expression. Gemcitabine-induced cytotoxicity was determined by MTT. Cell apoptosis was measured by flow cytometry. Caspase 3 activity was assayed using a Caspase Fluorescent Assay Kit. The effect of Notch3-specific siRNA on PI3K/Akt activity was also quantified. Notch3-specific siRNA suppressed Notch3 expression, and furthermore increased gemcitabine-induced, caspase-mediated apoptosis. The suppression of Notch3 expression decreased the average IC50 in BxPC-3 and PANC-1 cells treated with gemcitabine. PI3K/Akt activity was decreased by the suppression of Notch3 expression. Taken together, these data demonstrated that Notch3 is a potential therapeutic target for pancreatic cancer, and PI3K/Akt is a key signaling component by which activation of the Notch3 signal transduction pathway protects pancreatic cancer cells from chemotherapy-induced cell death.

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

Similar content being viewed by others

References

  1. Fryer RA, Galustian C, Dalgelish AG. Recent advances and developments in treatment strategies against pancreatic cancer. Curr Clin Pharmacol. 2009;4(2):102–12.

    Article  CAS  PubMed  Google Scholar 

  2. Jonckheere N, et al. Tumour growth and resistance to gemcitabine of pancreatic cancer cells are decreased by AP-2alpha overexpression. Br J Cancer. 2009;101(4):637–44.

    Article  CAS  PubMed  Google Scholar 

  3. Nickoloff BJ, Osborne BA, Miele L. Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents. Oncogene. 2003;22(42):6598–608.

    Article  CAS  PubMed  Google Scholar 

  4. Miyamoto A, Lau R, Hein PW, Shipley JM, Weinmaster G. Microfibrillar proteins MAGP-1 and MAGP-2 induce Notch1 extracellular domain dissociation and receptor activation. J Biol Chem. 2006;281(15):10089–97.

    Article  CAS  PubMed  Google Scholar 

  5. Radtke F, Wilson A, Mancini SJ, MacDonald HR. Notch regulation of lymphocyte development and function. Nat Immunol. 2004;5(3):247–53.

    Article  CAS  PubMed  Google Scholar 

  6. Maillard I, Adler SH, Pear WS. Notch and the immune system. 1. Immunity. 2003;19(6):781–91.

    Article  CAS  PubMed  Google Scholar 

  7. Maillard I, Fang T, Pear WS. Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu Rev Immunol. 2005;23:945–74.

    Article  CAS  PubMed  Google Scholar 

  8. Real PJ, Ferrando AA. NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia. 2009;23(8):1374–7.

    Article  CAS  PubMed  Google Scholar 

  9. Roy M, Pear WS, Aster JC. The multifaceted role of Notch in cancer. Curr Opin Genet Dev. 2007;17(1):52–9.

    Article  CAS  PubMed  Google Scholar 

  10. Dotto GP. Notch tumor suppressor function. Oncogene. 2008;27(38):5115–23.

    Article  CAS  PubMed  Google Scholar 

  11. Baek SH, et al. Zinc-induced downregulation of Notch signaling is associated with cytoplasmic retention of Notch1-IC and RBP-Jk via PI3k-Akt signaling pathway. Cancer Lett. 2007;255(1):117–26.

    Article  CAS  PubMed  Google Scholar 

  12. Meurette O, et al. Notch activation induces Akt signaling via an autocrine loop to prevent apoptosis in breast epithelial cells. Cancer Res. 2009;69(12):5015–22.

    Article  CAS  PubMed  Google Scholar 

  13. Kurreck J. RNA interference: from basic research to therapeutic applications. Angew Chem Int Ed Engl. 2009;48(8):1378–98.

    Article  CAS  PubMed  Google Scholar 

  14. Hu Y, et al. Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan. Mol Cancer Ther. 2009;8(8):2329–38.

    Article  CAS  PubMed  Google Scholar 

  15. Pauwels B, et al. The role of apoptotic cell death in the radiosensitising effect of gemcitabine. Br J Cancer. 2009;101(4):628–36.

    Article  CAS  PubMed  Google Scholar 

  16. Zhou H, Li XM, Meinkoth J, Pittman RN. Akt regulates cell survival and apoptosis at a postmitochondrial level. J Cell Biol. 2000;151(3):483–94.

    Article  CAS  PubMed  Google Scholar 

  17. Simon PO Jr, et al. Targeting AKT with the proapoptotic peptide, TAT-CTMP: a novel strategy for the treatment of human pancreatic adenocarcinoma. Int J Cancer. 2009;125(4):942–51.

    Article  CAS  PubMed  Google Scholar 

  18. Gramantieri L, et al. Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma. Liver Int. 2007;27(7):997–1007.

    Article  CAS  PubMed  Google Scholar 

  19. Doucas H, et al. Expression of nuclear Notch3 in pancreatic adenocarcinomas is associated with adverse clinical features, and correlates with the expression of STAT3 and phosphorylated Akt. J Surg Oncol. 2008;97(1):63–8.

    Article  PubMed  Google Scholar 

  20. Dang L, et al. Notch3 signaling initiates choroid plexus tumor formation. Oncogene. 2006;25(3):487–91.

    CAS  PubMed  Google Scholar 

  21. Akiyoshi T, et al. Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells. Gastroenterology. 2008;134(1):131–44.

    Article  CAS  PubMed  Google Scholar 

  22. Gazzaniga P, et al. Gemcitabine-induced apoptosis in 5637 cell line: an in vitro model for high-risk superficial bladder cancer. Anticancer Drugs. 2007;18(2):179–85.

    Article  CAS  PubMed  Google Scholar 

  23. Nefedova Y, Sullivan DM, Bolick SC, Dalton WS, Gabrilovich DI. Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood. 2008;111(4):2220–9.

    Article  CAS  PubMed  Google Scholar 

  24. Tassone P, et al. Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro. Br J Cancer. 2003;88(12):1971–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Medicine, Taizhou University, Jiaojiang District, 318000, Taizhou, Zhejiang, China

    Jun Yao

  2. Department of Gastroenterology, Taizhou Municipal Hospital, Jiaojiang District, 318000, Taizhou, Zhejiang, China

    Cuijuan Qian

Authors
  1. Jun Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cuijuan Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jun Yao or Cuijuan Qian.

Additional information

Jun Yao and Cuijuan Qian contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yao, J., Qian, C. Inhibition of Notch3 enhances sensitivity to gemcitabine in pancreatic cancer through an inactivation of PI3K/Akt-dependent pathway. Med Oncol 27, 1017–1022 (2010). https://doi.org/10.1007/s12032-009-9326-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-009-9326-5

Keywords

Search

Navigation