The Tumor Suppressor Activity of the Lysyl Oxidase Propeptide Reverses the Invasive Phenotype of Her-2/neu–Driven Breast Cancer

Abstract

Expression of the lysyl oxidase gene (LOX) was found to inhibit the transforming activity of the ras oncogene in NIH 3T3 fibroblasts and was hence named the ras recision gene (rrg). Lysyl oxidase (LOX) is synthesized and secreted as a 50-kDa inactive proenzyme (Pro-LOX), which is processed by proteolytic cleavage to a functional 32-kDa enzyme and an 18-kDa propeptide (LOX-PP). Recently, the ras recision activity of the LOX gene in NIH 3T3 cells was mapped to its propeptide region. Here, we show for the first time that LOX-PP inhibits transformation of breast cancer cells driven by Her-2/neu, an upstream activator of Ras. LOX-PP expression in Her-2/ neu-driven breast cancer cells in culture suppressed Akt, extracellular signal-regulated kinase, and nuclear factor-KB activation. Her-2/neu-induced epithelial to mesenchymal transition was reverted by LOX-PP, as judged by reduced levels of Snail and vimentin; up-regulation of E-cadherin, ;-catenin, and estrogen receptor A; and decreased ability to migrate or to form branching colonies in Matrigel. Furthermore, LOX-PP inhibited Her-2/neu tumor formation in a nude mouse xenograft model. Thus, LOX-PP inhibits signaling cascades induced by Her-2/neu that promote a more invasive phenotype and may provide a novel avenue for treatment of Her-2/neu-driven breast carcinomas. [Cancer Res 2007;67(3):1105-12]

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

“…Many studies have shown that increased LOX expression is associated with malignant progression of cancer cells [17,31,50], whereas some studies reported that 50-kDa pro-LOX or its cleaved 18-kDa product (LOX-PP) may have tumor-suppressive function [21][22][23][24]. One of the reasons responsible for the differences between these reports and our study might be the different the cell lines.…”

“…Involvement of the LOX family is widely accepted as a poor prognostic factor for patients with cancer [15][16][17][18][19][20]. By contrast, Kaneda et al [21] reported that LOX is a tumor suppressor gene inactivated by heavy methylation of the 5 0 untranslated region and loss of heterozygosity in gastric cancers, and several studies have reported that LOX-PP has tumor suppressor activity [22][23][24]. Both downregulation and upregulation of LOX in tumor tissues and cancer cell lines have been described [25][26][27][28], suggesting a paradoxical role for LOX as a tumor suppressor [21,29] as well as a metastasis promoter gene [30,31].…”

Lysyl oxidase propeptide inhibits smooth muscle cell signaling and proliferation

“…LOX is also a tumor suppressor and it inhibits ras-dependent transformation of fibroblasts [4,8,14]. The tumor suppressor activity of LOX has been mapped to the pro-peptide region [24] and LOX-PP inhibits tumor formation by breast cancer cells in mice [19]. In normal osteoblasts, LOX-PP accumulates in cultures [9] and recombinant LOX-PP is taken up by cells and accumulates over time associated with microtubules [7].…”

“…Primary vascular SMCs were grown with LOX-PP (10 μg/ml) or vehicle was then the number of viable cells per culture determined after 48 hours. The concentration of LOX-PP was based on preliminary dose response-and published studies [19,24,28]. Figure 1A shows that LOX-PP significantly inhibits the growth of SMC cultures.…”

“…Because LOX-PP is an effective inhibitor of Erk1/2 Map kinases [19,28], and this Map kinase mediates TNF-α stimulated SMC proliferation and MMP-9 expression [20], we determined whether LOX-PP inhibits vascular SMC proliferation and TNF-α stimulated MMP-9 expression, and whether LOX-PP directly inhibits the MEK/Erk enzymes. Finally, we determined whether LOX-PP is detectable in vivo in femoral arteries that had been subjected to guidewire injury and in sham controls.…”