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).