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


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 beta1 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.
Hehlgans
Stephanie
S
OncoRay-Center for Radiation Research in Oncology, Dresden University of Technology, Dresden, Germany.
Eke
Iris
I
Storch
Katja
K
Haase
Michael
M
Baretton
Gustavo B
GB
Cordes
Nils
N
D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000532:radiotherapy; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects*; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D010766:Phosphorylation / Q000235:genetics / Q000528:radiation effects; D011336:Probability; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013234:Stem Cells / Q000187:drug effects / Q000528:radiation effects; D014162:Transfection
D051242:Caveolin 1; D019012:Integrin beta1; D034741:RNA, Small Interfering