suppressor activity of LOX came from studies addressed to identify the genes involved in the IFN-c mediated-reversion of ras-transformed malignant cells. In these studies, a gene called ras recision gene was isolated and shown to be responsible for malignant reversion. In agreement with this, increased LOX expression was also found in spontaneous revertants of H-ras transformed rat fibroblasts while reduced LOX expression was observed in ras-transformed cells. In addition, Giampuzzi et al. reported that normal rat kidney fibroblasts in which LOX mRNA was knocked down by antisense lysyl oxidase showed loose attachment to the plate and anchorage-independent growth and were highly tumorigenic in nude mice. These findings evidence a role of LOX as a tumor suppressor, highlighting its particular role in controlling Ras activation and growth factor dependence. Palamakumbura et al, 16824511 described for the first time that the lysyl oxidase propeptide, but not the lysyl oxidase enzyme, was responsible for the inhibition of ras-dependent transformation of NIH3T3 cells as determined by effects on cell proliferation assays, growth in soft agar and Akt-dependent induction of NF-kappaB activity. Subsequently, LOX-PP was shown to act as a tumor suppressor in several cancer cells. For example, LOX-PP reverts the invasive phenotype of breast cancer cells, inhibits the transformed phenotype of lung and pancreatic cancer cells, interferes with FAK activation in breast cancer cells and inhibits prostate cancer cell growth by targeting FGF-2 cell purchase RS1 binding and signalling. The mechanism through LOX-PP act as a tumor suppressor begins now to be only partially understood. LOX-PP has been shown to impair both PI3K/Akt and ERK signalling pathways. Thus, ectopic pre-LOX and LOX-PP expression in H1299 lung cancer and PANC-1 pancreatic cancer cells inhibited growth in soft agar and migration and reduced activation of 
ERK and Akt, with LOX-PP showing substantially higher activity. In MIA PaCa-2, LOX-PP attenuated the ERK and Akt activities and decreased the levels of the NF-Kb p65 and RelB subunits and cyclin D1, which are activated by RAS signalling. Palamakumbura et al. showed that recombinant LOX-PP protein inhibits 12182951 serum-stimulated DNA synthesis and ERK and PI3K/Akt pathways in DU 145 and PC-3 androgen-independent cell lines. Our data indicate that the inhibition of proliferation observed upon LOX-PP expression in LOX-PP Supresses Ewing Sarcoma Tumorigenesis A673 Ewing cells could be mainly mediated by inhibition of the ERK pathway, while the PI3K/Akt pathway does not seem to be involved. Therefore, specific downstream targets of LOX-PP can depend on the cellular context. Studies carried out with gene expression microarrays shown as well that LOX-PP modified the expression of genes involved in specific pathways related to DNA synthesis and replication and cell cycle regulation, indicating that LOX-PP was clearly affecting cell proliferation. These results suggest that LOX-PP is affecting cell proliferation, first, by producing a significant inhibition of the ERK/MAPK pathway, and subsequently, by affecting pathways involved in cell cycle progression. In summary, in this work we shown that LOX is a gene repressed by the EWS/FLI1 oncoprotein and that its ectopic reexpression in an Ewing cell line inhibits cell proliferation. We also shown that this function is attributed to the LOX propeptide, an N-terminal fragment of the LOX protein released during processing, which in