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Blocking a6 integrin cleavage as a therapeutic target for prostate cancer bone metastases

Objective

Prostate cancer affects people all over the world. The most frequent site of prostate cancer metastasis is the bone and once it has metastasised it is incurable and extremely painful. The goal of this proposal is to develop new therapeutic tools for palliative care for bone metastases. Our model states that the high levels of uPA in the bone induce cleavage of the a6 integrin in prostate cancer cells, leading to the activation of other integrins (such as a2, a3 and av) to allow for migration and homing on the bone matrix. In this proposal, we will investigate whether the a6 integrin cleavage by uPA controls cell adhesion by integrins other than the a6 integrin, a process referred to as "integrin switching".

In addition, we will investigate whether the a6 integrin cleavage by uPA controls migration through focal adhesion signalling. First, we will test the hypothesis that blocking the cleavage of the a6 integrin will reduce osteoblast conditioned media (OBCM) induced adhesion of prostate cancer cells on b one matrix. We will test this by using a peptide and an antibody designed to prevent a6 integrin cleavage and we will also perform transfections of an uncleavable a6 integrin mutant in the PC3 prostate cancer cell line. We will evaluate changes in adhesio n on different substrates (collagen, vitronectin and osteopontin) using cell adhesion assays. Second, we will test the hypothesis that blocking the cleavage (using a peptide, an antibody and transfections) of the a6 integrin will reduce the phosphorylation levels of FAK, Pax and p130CAS upon OBCM stimulation.

Third, using the peptide, the antibody and the transfections in the PC3 cell line, we will investigate the role of the a6 integrin cleavage by uPA in cell migration and invasion upon OBCM stimulation . Migration will be measured using the Cell Sedimentation Manifold (CSM), and the scratch assay, and invasion using the Boyden chamber method.

Call for proposal

FP6-2004-MOBILITY-12
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Coordinator

UNIVERISTY OF CYPRUS
Address
Kallipoleos 75
Nicosia
Cyprus