p27(kip1) acts as a downstream effector of and is coexpressed with the β(1C) integrin in prostatic adenocarcinoma

Abstract

Integrins are a large family of transmembrane receptors that, in addition to mediating cell adhesion, modulate cell proliferation. The β(1C) integrin is an alternatively spliced variant of the β1 subfamily that contains a unique 48-amino acid sequence in its cytoplasmic domain. We have shown previously that in vitro β(1C) inhibits cell proliferation and that in vivo β(1C) is expressed in nonproliferative, differentiated epithelium and is selectively downregulated in prostatic adenocarcinoma. Here we show, by immunohistochemistry and immunoblotting analysis, that β(1C) is coexpressed in human prostate epithelial cells with the cell-cycle inhibitor p27(kip1), the loss of which correlates with poor prognosis in prostate cancer. In the 37 specimens analyzed, β(1C) and p27(kip1) are concurrently expressed in 93% of benign and 84%-91% of tumor prostate cells. Forced expression of β(1C) in vitro is accompanied by an increase in p27(kip1) levels, by inhibition of cyclin A-dependent kinase activity, and by increased association of p27(kip1) with cyclin A. β(1C) inhibitory effect on cell proliferation is completely prevented by p27(kip1) antisense, but not mismatch oligonucleotides. β(1C) expression does not affect either cyclin A or E levels, or cyclin E- associated kinase activity, nor the mitogen-activated protein (MAP) kinase pathway. These findings show a unique mechanism of cell growth inhibition by integrins and point to β(1C) as an upstream regulator of p27(kip1) expression and, therefore, a potential target for tumor suppression in prostate cancer.