Caveolin-1 Contributes To Regulation Of Radiation Survival Via The B1 Integrin/AKT Signaling Axis

Main Category: Radiology / Nuclear Medicine
Also Included In: Cancer / Oncology
Article Date: 22 Sep 2008 - 4:00 PDT

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The integral membrane protein Caveolin-1 forms small invaginations of the plasma membrane, so-called caveolae, for serving in endo-exocytosis and is involved in regulating signaling from integrins and receptor-tyrosine kinases. Both, integrins and receptor-tyrosine kinases, are considered to confer radioresistance and chemoresistance of tumours. Integrins are responsible for interactions of cells with their surrounding extracellular matrix, transmit extracellular signals to control survival, proliferation or apoptosis, and have been demonstrated to transduce prosurvival signals via the cytoplasmic protein kinase AKT. The aim of this study was to evaluate the distinct role of Caveolin-1 in radiation survival of human pancreatic tumor cells and its putative interaction with the widely expressed ß1 integrin using a three-dimensional (3D) cell culture model, which mimics physiological growth conditions in contrast to the conventional 2D cell culture.

Caveolin-1 overexpressing or Caveolin-1 siRNAtransfected pancreatic tumor cells were grown in a 3D laminin-rich extracellular matrix, irradiated (0-6 Gy, X-rays) and subjected to 3D clonogenic assays. The potential involvement of a range of signaling proteins in regulating cellular radiation survival were analyzed by Western blotting, immunoprecipitation and intracellular tracking of Caveolin-1-GFPand fluorochrome-labeled monoclonal anti-ß1 integrin antibodies.

Overexpression of Caveolin-1 improved clonogenic radiation survival of 3D grown cell lines while siRNA-mediated Caveolin-1 knockdown resulted in significantly (p<0.01) enhanced radiosensitivity as compared to corresponding controls. Analysis of Caveolin-1 associated signaling pathways revealed a strong downregulation of both ß1 integrin expression and phosphorylated AKT S473. Immunofluorescence tracking assays demonstrated Caveolin-1/ß1 integrin colocalization in Caveolae.

Our results provide evidence for Caveolin-1 as a strong modulator of cellular radiosensitivity in a three-dimensional cell culture model. This is the first report showing an interaction of Caveolin-1 with both, the cell-adhesion molecule ß1 integrin and the prosurvival regulator AKT, that decisively impact on radioresistance of pancreatic tumour cells. The understanding of the underlying molecular mechanisms might promote the development of targeted approaches against Caveolin-1 administrated in combination with conventional radio- and chemotherapeutic strategies.

Hehlgans Stephanie et al. OncoRay , Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden , Germany

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