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CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic cancer
  1. S Ripka1,
  2. A Neesse1,
  3. J Riedel1,
  4. E Bug1,
  5. A Aigner2,
  6. R Poulsom3,
  7. S Fulda4,
  8. J Neoptolemos5,
  9. W Greenhalf5,
  10. P Barth6,
  11. T M Gress1,
  12. P Michl1
  1. 1Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University, Marburg, Germany
  2. 2Department of Pharmacology and Toxicology, Philipps-University, School of Medicine, Marburg, Germany
  3. 3Cancer Research UK, London Research Institute, London, UK
  4. 4University Children's Hospital, Ulm University, Germany
  5. 5Department of Surgery, University of Liverpool, Liverpool, UK
  6. 6Institute of Pathology, Philipps-University, School of Medicine, Marburg, Germany
  1. Correspondence to Dr Patrick Michl, Department of Gastroenterology, University of Marburg, Baldinger Strasse, D-35043 Marburg, Germany; michlp{at}med.uni-marburg.de

Abstract

Background and aims The transcription factor CUX1 is known as a regulator of cell differentiation and cell cycle progression. Previously, CUX1 was identified as a modulator of invasiveness in various cancers. Based on expression profiles suggesting a role for CUX1 in mediating chemoresistance, the aim of this study was to characterise the effect of CUX1 on apoptosis as well as its regulation by signalling pathways modulating drug resistance in pancreatic cancer.

Methods The effect of CUX1 on TRAIL- (tumour necrosis factor-related apoptosis-inducing ligand) and drug-induced apoptosis was analysed using overexpression and knock-down strategies. Regulation of CUX1 by phosphatidylinositol-3-kinase (PI3K)/Akt signalling was examined at the mRNA and protein level. The effect of CUX1 knock-down by nanoparticle-complexed small interfering RNA (siRNA) in vivo was analysed in a murine xenograft model. Furthermore, CUX1 RNA and protein expression was evaluated in human pancreatic cancer and adjacent normal tissues.

Results Knock-down of CUX1 resulted in significantly enhanced TRAIL- and drug-induced apoptosis, associated with increased PARP (poly ADP-ribose polymerase) cleavage and caspase activity. Vice versa, overexpression of CUX1 inhibited apoptosis. CUX1 expression was induced by activation of Akt/protein kinase B signalling, and decreased by PI3K inhibitors. The antiapoptotic effect of CUX1 was associated with upregulation of BCL2 and downregulation of tumour necrosis factor α. CUX1 was significantly overexpressed in pancreatic cancers, as analysed by in situ hybridisation and immunohistochemistry. In vivo, silencing of CUX1 by intratumourally administered polyethylenimine-complexed siRNA led to reduced tumour growth and increased apoptosis in pancreatic cancer xenografts.

Conclusion CUX1 was identified as an important mediator of tumour cell survival in pancreatic cancer in vitro and in vivo.

  • Akt
  • apoptosis
  • CUX1
  • drug resistance
  • molecular oncology
  • pancreatic cancer

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Footnotes

  • Linked articles 206854.

  • Funding This work was supported in part by grants of the Deutsche Forschungsgemeinschaft (DFG) (to PM), the Behring-Roentgen Foundation (to PM), the Deutsche Krebshilfe (to AA) and the European Commisson FP6 grant LSHB-CT-2006-018771 (Integrated Project ‘MolDiag-Paca’, to TG). This publication reflects only the authors' views. The European Community is not liable for any use that may be made of the information herein.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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