The Antitumor Peptide CIGB-552 Increases COMMD1 and Inhibits Growth of Human Lung Cancer Cells

Abstract

We have demonstrated that the peptide L-2 designed from an alanine scanning of the Limulus-derived LALF32-51 region is a potential candidate for the anticancer therapy and its cell-penetrating capacity is an associated useful property. By the modification in the primary structure of L-2, a second-generation peptide (CIGB-552) was developed. However, the molecular mechanism underlying its cytotoxic activity remains partially unknown. In this study, it was shown that CIGB-552 increases the levels of COMMD1, a protein involved in copper homeostasis, sodium transport, and the NF-κB signaling pathway. We found that CIGB-552 induces ubiquitination of RelA and inhibits the antiapoptotic activity regulated by NF-κB, whereas the knockdown of COMMD1 blocks this effect. We also found that CIGB-552 decreases the antioxidant capacity and induces the peroxidation of proteins and lipids in the tumor cells. Altogether, this study provides new insights into the mechanism of action of the peptide CIGB-552, which could be relevant in the design of future anticancer therapies.

Comparative proteomics analysis of the antitumor effect of CIGB-552 peptide in HT-29 colon adenocarcinoma cells

“…Treatment of H460 cells has a pro-apoptotic effect dependent on NF-κB signaling negative regulation and cell redox capacity impairment [5]. Correspondingly, here we detected using a bioinformatics-driven analysis the differential modulation of proteins associated to apoptosis and oxidative damage and to other processes such as metastasis and inflammation (See Table 3 in …”

“…A suppressive subtractive hybridization (SSH) analysis on laryngeal tumor Hep2 cells showed that L-2 peptide treatment impacts the expression of genes that function in cancer related biological processes and pathways such as: DNA repair, mitosis, and angiogenesis [4]. Furthermore, a yeast two-hybrid study of CIGB-552 interactome identified COMMD1 protein as a target of CIGB-552 [5]. The importance of COMMD1 was later assessed by siRNA in H460 non-small cell lung cancer cells, with COMMD1 knockdown cells displaying a significant decrease in peptide cytotoxicity compared with control [5]; noticeably, peptide effect wasn't completely abrogated reflecting the occurrence of COMMD1-independent events.…”

“…Furthermore, a yeast two-hybrid study of CIGB-552 interactome identified COMMD1 protein as a target of CIGB-552 [5]. The importance of COMMD1 was later assessed by siRNA in H460 non-small cell lung cancer cells, with COMMD1 knockdown cells displaying a significant decrease in peptide cytotoxicity compared with control [5]; noticeably, peptide effect wasn't completely abrogated reflecting the occurrence of COMMD1-independent events.…”

“…CIGB-552 peptide stimulation induces cytotoxicity in different cancer cell lines with human colon adenocarcinoma and non-small cell lung cancer cells showing the highest sensitivities [4,5]. Treatment of H460 cells has a pro-apoptotic effect dependent on NF-κB signaling negative regulation and cell redox capacity impairment [5].…”

“…Among peptides, L-2 displayed the strongest in vitro cytotoxicity in human and mouse cancer cell lines [4]. The L-2 peptide primary structure was further modified to improve its activity and specificity yielding the second generation peptide CIGB-552 [5,6].…”