ABSTRACT
Peptide-based cancer therapy has been of great interest due to the unique advantages of peptides, such as their low MW, the ability to specifically target tumour cells, easily available and low toxicity in normal tissues. Therefore, identifying and synthesizing novel peptides could provide a promising option for cancer patients. The antitumour second generation peptide, CIGB-552 has been developed as a candidate for cancer therapy. Proteomic and genomic studies have identified the intracellular protein COMMD1 as the specific target of CIGB-552. This peptide penetrates to the inside tumour cells to induce the proteasomal degradation of RelA, causing the termination of NF-κB signalling. The antitumour activity of CIGB-552 has been validated in vitro in different human cancer cell lines, as well as in vivo in syngeneic and xenograft tumour mouse models and in dogs with different types of cancers. The aim of this review is to present and discuss the experimental data obtained on the action of CIGB-552, including its mechanism of action and its therapeutic potential in human chronic diseases. This peptide is already in phase I clinical trials as antineoplastic drug and has also possible application for other inflammatory and metabolic conditions.
Subject(s)
Antineoplastic Agents , Cell-Penetrating Peptides , Neoplasms , Adaptor Proteins, Signal Transducing , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Dogs , Horseshoe Crabs , Humans , Mice , Neoplasms/drug therapy , ProteomicsABSTRACT
CIGB-552 is a synthetic anti-tumor peptide capable of reducing tumor size and increasing the lifespan of tumor-bearing mice. Part of its anti-cancer effects consists of inducing apoptosis, modulating NF-kB signaling pathway, and the angiogenesis process. Although one of its major mediators, the COMMD1 protein, has been identified, the mechanism by which CIGB-552 exerts such effects remains elusive. In the present study, we show the role of COMMD1 in CIGB-552 mechanism of action by generating the COMMD1 knock-out from the human lung cancer cell line NCI-H460. A microarray was performed to analyze both wild-type and KO cell lines with regard to CIGB-552 treatment. Additionally, different signaling pathways were studied in both cell lines to validate the results. Furthermore, the interaction between CIGB-552 and COMMD1 was analyzed by confocal microscopy. By signaling pathway analysis we found that genes involved in cell proliferation and apoptosis, oncogenic transformation, angiogenesis and inflammatory response are potentially regulated by the treatment with CIGB-552. We then demonstrated that CIGB-552 is capable of modulating NF-kB in both 2D and 3D cell culture models. Finally, we show that the ability of CIGB-552 to negatively modulate NF-kB and HIF-1 pathways is impaired in the COMMD1 knock-out NCI-H460 cell line, confirming that COMMD1 is essential for the peptide mechanism of action.
Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Angiogenesis Inhibitors/pharmacology , Anti-Inflammatory Agents/pharmacology , Cell-Penetrating Peptides/pharmacology , Colonic Neoplasms/drug therapy , Inflammation/drug therapy , Lung Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Animals , Apoptosis , Cell Proliferation , Colonic Neoplasms/blood supply , Colonic Neoplasms/immunology , Colonic Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Lung Neoplasms/blood supply , Lung Neoplasms/immunology , Lung Neoplasms/metabolism , Mice , Mice, Knockout , NF-kappa B/metabolism , Neovascularization, Pathologic/immunology , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Tumor Cells, CulturedABSTRACT
CIGB-552 is a cell-penetrating peptide that exerts in vitro and in vivo antitumor effect on cancer cells. In the present work, the mechanism involved in such anticancer activity was studied using chemical proteomics and expression-based proteomics in culture cancer cell lines. CIGB-552 interacts with at least 55 proteins, as determined by chemical proteomics. A temporal differential proteomics based on iTRAQ quantification method was performed to identify CIGB-552 modulated proteins. The proteomic profile includes 72 differentially expressed proteins in response to CIGB-552 treatment. Proteins related to cell proliferation and apoptosis were identified by both approaches. In line with previous findings, proteomic data revealed that CIGB-552 triggers the inhibition of NF-κB signaling pathway. Furthermore, proteins related to cell invasion were differentially modulated by CIGB-552 treatment suggesting new potentialities of CIGB-552 as anticancer agent. Overall, the current study contributes to a better understanding of the antitumor action mechanism of CIGB-552.
Subject(s)
Cell-Penetrating Peptides/administration & dosage , Cell-Penetrating Peptides/chemistry , Neoplasm Proteins/chemistry , Neoplasm Proteins/metabolism , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Amino Acid Sequence , Binding Sites , Cell Line, Tumor , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/drug effects , Humans , Molecular Sequence Data , Neoplasms, Experimental/genetics , Protein Binding , Protein Interaction Mapping/methods , Proteome/chemistry , Proteome/metabolism , Proteomics/methods , Sequence Analysis, Protein/methods , Treatment OutcomeABSTRACT
CIGB-552 is a second generation antitumor peptide that displays potent cytotoxicity in lung and colon cancer cells. The nuclear subproteome of HT-29 colon adenocarcinoma cells treated with CIGB-552 peptide was identified and analyzed [1]. This data article provides supporting evidence for the above analysis.
ABSTRACT
The second generation peptide CIGB-552 has a pro-apoptotic effect on H460 non-small cell lung cancer cells and displays a potent cytotoxic effect in HT-29 colon adenocarcinoma cells though its action mechanism is ill defined. Here, we present the first proteomic study of peptide effect in HT-29 cells using subcellular fractionation, protein and peptide fractionation by DF-PAGE and LC-MS/MS peptide identification. In particular, we explored the nuclear proteome of HT-29 cells at a 5h treatment identifying a total of 68 differentially modulated proteins, 49 of which localize to the nucleus. The differentially modulated proteins were analyzed following a system biology approach. Results pointed to a modulation of apoptosis, oxidative damage removal, NF-κB activation, inflammatory signaling and of cell adhesion and motility. Further Western blot and flow-cytometry experiments confirmed both pro-apoptotic and anti-inflammatory effects of CIGB-552 peptide in HT-29 cells.