Role of Alpha(v)Beta6-Mediated Latent TGF(Beta)1 Activation in Prostate Cancer

摘要

Abundant evidence suggests that overexpression of TGFBeta by prostate cancer cells enhances their ability to grow and metastasize. TGFBeta is secreted by cells in a latent form that results from a noncovalent interaction between TGF-Beta and its propeptide (latency- associated peptide, LAP). Mechanisms leading to active TGF-Beta are poorly understood at present. Our lab discovered a mechanism of TGF-Beta1 activation in which the integrin alphaVBeta6 binds to an RGD sequence near the C-terminus of LAP. alphaVBeta6 is only expressed in epithelial ells. The hypothesize that alphaVBeta6, by activating TGF-Betal, is an important regulator of normal prostate epithelial proliferation, and that overexpression of alphaVBeta6 by prostate tumor cells cts in concert with overexpression of its ligand latent TGF-Betal to produce active TGF-Betal and promote growth of the tumor In this work, we are testing whether the Beta6 integrin subunit is regulated by androgen, whether it is overexpressed in human prostate cancer, and whether it affects growth and metastasis of prostate cancer in an animal model. Our results to date indicate that Beta6 expression is upregulated in the mouse in a delayed fashion after castration. We are now testing whether castration-induced prostate involution is affected by Beta6 by comparing normaland 136 KO animals, and producing mice that develop prostate cancer (TRAMP) that also lack 86 gene expression.