Caveolin-1 mediated radioresistance of 3D grown pancreatic cancer cells
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.
aOncoRay – Center for Radiation Research in Oncology, Dresden University of Technology, Dresden, Germany
bDepartment Children’s Surgery, Dresden University of Technology, Dresden, Germany
cDepartment of Pathology, 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.
ABSTRACT