No abstract

Neoangiogenesis is essential for tumor and metastasis growth, but this complex process does not follow the same activation pathway, at least in tumor cell lines originated from different murine mammary adenocarcinomas. LMM3 cells were the most potent to stimulate new blood vessel formation. This response was significantly reduced by preincubating cells with indomethacin and NS-398, non-selective cyclooxygenase (COX) and COX-2 selective inhibitors, respectively. COX-1 and COX-2 isoenzymes were both highly expressed in LMM3 cells, and we observed that indomethacin was more effective than NS-398 to inhibit prostaglandin E2 (PGE2) synthesis. In addition, nitric oxide synthase (NOS) inhibitors, Nomega monomethyl L-arginine and aminoguanidine, also reduced LMM3-induced angiogenesis and nitric oxide (NO) synthesis as well. NOS2 > NOS3 proteins and arginase II isoform were detected in LMM3 cells by Western blot. The latter enzyme was also involved in the LMM3 neovascular response, since the arginase inhibitor, Nomega hydroxy L-arginine reduced the angiogenic cascade. On the other hand, parental LM3 cells were able to stimulate neovascularization via COX-1 and arginase products since only indomethacin and Nomega hydroxy L-arginine, which diminished PGE2 and urea synthesis, respectively, also reduced angiogenesis. In turn, LM2 cells angiogenic response could be due in fact to PGE2-induced VEGF liberation that stimulated neoangiogenesis at very low levels of NO.

2-Cys peroxiredoxins (2-Cys Prxs) are ubiquitous enzymes that have been implicated in peroxide-mediated signaling of markedly different processes, such as cancer and photosynthesis. A highly conserved C-terminal extension of eukaryotic homologues modulates both the overoxidation of cysteines and the formation of oligomers. Here, we reveal that the plant counterpart regulates the self-polymerization of 2-Cys Prx triggered by ATP and Mg(2+). This feature is of particular importance under oxidative stress because the interaction of ATP with 2-Cys Prx rapidly integrates nonredox chemistry of signaling pathways into a network hub governed by multiple redox transformations at cysteine residues.