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-kappaB 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, gamma-catenin, and estrogen receptor alpha; 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.
Highlights
The enzyme lysyl oxidase (LOX) catalyzes oxidative modifications that promote formation of lysine-derived covalent cross-links needed for the normal structural integrity of the extracellular matrix [1, 2]
We tested the effects of lysyl oxidase gene (LOX)-PP and LOX on NIH 3T3 cells transformed by H-Ras (3T3-Ras)
We show for the first time that lysyl oxidase propeptide (LOX-PP) functions as a tumor suppressor in breast cancer cells both in vitro and in vivo, and reverts the invasive phenotype of Her-2/neu–driven cancer cells
Summary
The enzyme lysyl oxidase (LOX) catalyzes oxidative modifications that promote formation of lysine-derived covalent cross-links needed for the normal structural integrity of the extracellular matrix [1, 2]. We showed that ectopic expression of Pro-LOX in rastransformed NIH 3T3 cells inhibits the activities of phosphatidylinositol 3-kinase, Akt, extracellular signal–regulated kinase (Erk) 1/2, and nuclear factor-nB We reported that, unexpectedly, it is LOX-PP, and not the LOX enzyme, that inhibits ras-dependent transformation of NIH 3T3 fibroblasts as determined by effects on proliferation, growth in soft agar, and ras-dependent signaling that induces NF-nB activity [16]. These findings identify the 18-kDa LOX-PP as a novel inhibitor of rasmediated transformation of fibroblasts
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