The lysyl oxidase pro-peptide attenuates fibronectin-mediated activation of the focal adhesion kinase and p130Cas in breast cancer cells.

Abstract

Abstract Abstract #4073 The lysyl oxidase (LOX) gene encodes an enzyme (LOX) critical for extracellular matrix maturation. The LOX gene has also been shown to inhibit the transforming activity of Ras oncogene signaling. In particular, the pro-peptide domain (LOX-PP) of the secreted precursor protein (Pro-LOX) was found to inhibit the transformed phenotype of breast, lung and pancreatic cancer cells. LOX-PP expression in these carcinoma cells reverted Her-2/neu- and Ras-mediated epithelial to mesenchymal transition (EMT), leading to increased expression of E-cadherin and γ-catenin, and reduced levels of Snail, vimentin and/or BCL2, as well as invasion through Matrigel. Furthermore, LOX-PP expression reduced tumor formation of Her-2/neu driven breast cancer cells in a xenograft model. However, the mechanism of action remains to be determined. Here the ability of LOX-PP to attenuate the integrin signaling pathway in NF639 breast cancer cells driven by Her-2/neu, which signals via Ras, was tested. Ectopic Pro-LOX and LOX-PP expression inhibited fibronectin-stimulated protein tyrosine phosphorylation. Importantly, phosphorylation of the focal adhesion kinase (FAK) on Tyr397 and Tyr576, and the activation of its downstream target p130Cas were substantially reduced. Furthermore, these changes were also reflected by a reduced amount of endogenous p130Cas in the Triton X-100 insoluble protein fraction, and attenuation of fibronectin-activated haptotaxis. Interestingly, expression of mature LOX enzyme enhanced fibronectin-stimulated integrin signaling. Of note, treatment with recombinant LOX-PP reduced haptotaxis of NF639 and human MDA-MB-231 and Hs578T breast cancer cells. Thus, the tumor suppressor function of LOX-PP is likely mediated, in part, by blocking integrin signaling and fibronectin-stimulated cell migration. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4073.