P02.05 - Pharmacological Stabilization of Commd1 Mediated by CIGB-552 Regulates NF-KB/Oxidative Stress Signaling and Inhibits Lung Cancer Cells Growth

Abstract

We have demonstrated that a novel peptide designed from an Alanine scanning of the Limulus-derived LALF32-51 region is a potential candidate for anticancer therapy. The peptide L-2 shows antineoplastic effect in a variety of tumor cell lines and its cell-penetrating capacity is an useful property associated. By modification in the primary structure of L-2 we have developed a second-generation peptide (CIGB-552) as anticancer drug. However, the molecular mechanism by which the CIGB-552 exhibits cytotoxic activity in cancer cells remain incompletely defined. In this study, we show that CIGB-552 increases the levels of COMMD1, a protein involved in copper homeostasis, sodium transport and the NF-kB signaling pathway. We found that CIGB-552 induces ubiquitination of RelA and inhibits the anti-apoptotic genes regulated by NF-kB whereas knockdown of COMMD1 blocks this effect. Concomitantly, microarrays profiling of lung cancer cells treated with CIGB-552 identified the expression of many genes involve in the oxidative stress response, cell growth arrest and DNA-damage inducible. Mechanistically, our studies show that CIGB-552 regulates the anti-apoptotic activity of NF-kB and induces an imbalance of the antioxidant defenses, promoting cell cycle arrest and apoptosis in lung cancer cells. Interestingly, the peptides derived from LALF32−51 region were found to bind COMM domain (amino acids 119-190) and, more important, our results provide the first indication that CIGB-552 could regulate the levels of COMMD1 to induce the cell death in cancer cells.