Human pancreatic tumor cells are sensitized to ionizing radiation by knockdown of caveolin-1.
Caveolin-1 (Cav-1) is an integral transmembrane protein and a critical component in interactions of integrin receptors with cytoskeleton-associated and signaling molecules. Since integrin-mediated cell adhesion generates signals conferring radiation resistance, we examined the effects of small interfering RNA-mediated knockdown of Cav-1 alone or in combination with beta1-integrin or focal adhesion kinase (FAK) on radiation survival and proliferation of pancreatic carcinoma cell lines. Irradiation induced Cav-1 expression in PATU8902, MiaPaCa2 and Panc1 cell lines. The cell lines showed significant radiosensitization after knockdown of Cav-1, beta1-integrin or FAK and cholesterol depletion by beta-cyclodextrin relative to nonspecific controls. Under knockdown conditions, proliferation of non-irradiated and irradiated cells was significantly attenuated relative to controls. These findings correlated with changes in expression or phosphorylation of Akt, glycogen synthase kinase 3beta, Paxillin, Src, c-Jun N-terminal kinase and mitogen-activated protein kinase. Analysis of DNA microarray data revealed a Cav-1 overexpression in a subset of pancreatic ductal adenocarcinoma samples. The data presented show, for the first time, that disruption of interactions of Cav-1 with beta1-integrin or FAK affects radiation survival and proliferation of pancreatic carcinoma cells and suggest that Cav-1 is critical to these processes. These results indicate that strategies targeting Cav-1 may be useful as an approach to improve conventional therapies, including radiotherapy, for pancreatic cancer.
Cordes
N
N
OncoRay - Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden, University of Technology, Dresden, Germany. nils.cordes@oncoray.de
Frick
S
S
Brunner
T B
TB
Pilarsky
C
C
Grützmann
R
R
Sipos
B
B
Klöppel
G
G
McKenna
W G
WG
Bernhard
E J
EJ
D015153:Blotting, Western; D051242:Caveolin 1 / Q000378:metabolism*; D002448:Cell Adhesion; D002453:Cell Cycle / Q000502:physiology / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D003114:Colony-Forming Units Assay; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D019012:Integrin beta1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D051419:Paxillin / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011836:Radiation Tolerance / Q000502:physiology*; D015398:Signal Transduction; D014965:X-Rays
D051242:Caveolin 1; D019012:Integrin beta1; D051419:Paxillin; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases