Caveolin-1 mediated radioresistance of 3D grown pancreatic cancer cells

Hehlgans, Stephanie; Eke, Iris; Storch, Katja; Haase, Michael; Baretton, Gustavo B.; Cordes, Nils

doi:10.1016/j.radonc.2009.07.004

« Previous Next »Radiotherapy & Oncology
Volume 92, Issue 3 , Pages 362-370, September 2009

Caveolin-1 mediated radioresistance of 3D grown pancreatic cancer cells

Stephanie Hehlgans
- OncoRay – Center for Radiation Research in Oncology, Dresden University of Technology, Dresden, Germany
Iris Eke
- OncoRay – Center for Radiation Research in Oncology, Dresden University of Technology, Dresden, Germany
Katja Storch
- OncoRay – Center for Radiation Research in Oncology, Dresden University of Technology, Dresden, Germany
Michael Haase
- Department Children’s Surgery, Dresden University of Technology, Dresden, Germany
- Department of Pathology, Dresden University of Technology, Dresden, Germany
Gustavo B. Baretton
- Department of Pathology, Dresden University of Technology, Dresden, Germany
Nils Cordes
- OncoRay – Center for Radiation Research in Oncology, Dresden University of Technology, Dresden, Germany
- Corresponding author. Address: OncoRay – Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Fetscherstrasse 74/PF 86, 01307 Dresden, Germany.

Received 22 April 2009; received in revised form 30 June 2009; accepted 3 July 2009. published online 10 August 2009.

Abstract

Background and purpose

Resistance of pancreatic ductal adenocarcinoma (PDAC) to chemo- and radiotherapy is a major obstacle. The integral membrane protein Caveolin-1 (Cav-1) has been suggested as a potent target in human pancreatic carcinoma cells.

Materials and methods

Human pancreatic tumor cells were examined in a three-dimensional (3D) cell culture model with regard to clonogenic survival, apoptosis, radiogenic DNA-double strand breaks and protein expression and phosphorylation under siRNA-mediated knockdown of Cav-1 without and in combination with irradiation (X-rays, 0–6Gy). Immunohistochemistry was used to assess Cav-1 expression in biopsies from patients with PDAC.

Results

Tumor cells in PDAC showed significantly higher Cav-1 expression relative to tumor stroma. Cav-1 knockdown significantly reduced β1 integrin expression and Akt phosphorylation, induced Caspase 3- and Caspase 8-dependent apoptosis and enhanced the radiosensitivity of 3D cell cultures. While cell cycling and Cav-1 promoter activity remained stable, Cav-1 knockdown-induced radiosensitization correlated with elevated numbers of residual DNA-double strand breaks.

Conclusions

Our data strongly support the concept of Cav-1 as a potent target in pancreatic carcinoma cells due to radiosensitization and Cav-1 overexpression in tumor cells of PDAC. 3D cell cultures are powerful and useful tools for the testing of novel targeting strategies to optimize conventional radio- and chemotherapy regimes for PDAC.

Abbreviations: Cav-1, Caveolin-1, DNA-DSB, DNA-double strand break, ECM, extracellular matrix, FAK, focal adhesion kinase, GSK3β, glycogen synthase kinase-3β, ILK, integrin-linked kinase, IP, immunoprecipitation, lrECM, laminin-rich extracellular matrix, PINCH-1, particularly interesting new cysteine–histidine-rich protein 1, rDNA-DSB, residual DNA-double strand break