COMMD1 and NF-κB activity
The COMMD protein family is highly conserved among multicellular eukaryotic organisms. COMMD1 is the best characterized member of the family and is conserved among vertebrates (Burstein et al., 2005). This protein represents a pleiotropic factor involved in the regulation of many cellular and physiological processes that include oxidative stress, protein aggregation, protein trafficking, NF-κB-mediated transcription and oncogenesis (Bartuzi et al., 2016; Phillips-Krawczak et al., 2015; Vonk et al., 2010). The potential of COMMD1 in cancer therapy is becoming a focus of attention and this protein offers a way to modulate crucial events in oncogenesis and even produces ROS that contribute with apoptosis of tumor cells, in a safe and specific manner (Riera-Romo, 2018).
The proteomics and genomics approach indicated that COMMD1 represents a molecular target of the peptide CIGB-552. The development of the interactome of CIGB-552, where the data obtained by genomics and proteomics study was integrated, suggests a direct connection with the NF-κB pathway, in a COMMD1-dependent manner. According to these findings, the cellular expression of COMMD1 in whole-cell lysates of human cancer cells of different histological origin was determined using Western blot analysis. These experiments revealed an increase in the levels of endogenous COMMD1 after five hours of treatment with the peptide (Fernandez Masso et al., 2013). This effect on COMMD1 was not accompanied by significant changes in mRNA expression of the protein, suggesting a posttranscriptional effect of CIGB-552 on COMMD1 levels (Fernandez Masso et al., 2013). It is known that nuclear localization of the protein COMMD1 accelerates the ubiquitination and degradation of the RelA subunit of NF-κB and decreases the activation of antiapoptotic genes (Maine, Mao, Komarck, & Burstein, 2007; Thoms et al., 2010). In this sense, we demonstrated that in response to CIGB-552, COMMD1 localizes into the nucleus, a fact that is related with increasing amounts of ubiquitinated RelA and apoptosis induction (Figure 3). This effect was abrogated decreasing the levels of COMMD1 by interferent RNA (iRNA) gene silencing method (knockdown), indicating the functional role of this protein in the antitumor activity of CIGB-552 (Fernandez Masso et al., 2013).
As a downstream event, the transcriptional activity of NF-κB was evaluated in the reporter cell line HT-29-NF-κB-hrGFP E5. The peptide CIGB-552 inhibits the NF-κB activity in these cells in presence or absence of proinflammatory cytokines such as TNF-α and IL-1β. Besides, CIGB-552 reduces the levels of IL-8 in cell culture supernatants confirming the inhibition of NF-κB activity (Nunez de Villavicencio-Diaz et al., 2015).