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Plakophilin 1 (PKP1), a member of the armadillo repeat family of proteins, is a key structural component of cell-cell adhesion scaffolds, although it can also be found in other cell locations, including the cytoplasm and the nucleus. PADI4 (peptidyl-arginine deiminase 4) is one of the human isoforms of a family of enzymes engaged in the conversion of arginine to citrulline, and is present in monocytes, macrophages, granulocytes, and in several types of cancer cells. It is the only family member observed both within the nucleus and the cytoplasm under ordinary conditions. We studied the binding of the armadillo domain of PKP1 (ARM-PKP1) with PADI4, by using several biophysical methods, namely fluorescence, far-ultraviolet (far-UV) circular dichroism (CD), isothermal titration calorimetry (ITC), and molecular simulations; furthermore, binding was also tested by Western-blot (WB) analyses. Our results show that there was binding between the two proteins, with a dissociation constant in the low micromolar range (∼ 1 μM). Molecular modelling provided additional information on the possible structure of the binding complex, and especially on the binding hot-spot predicted for PADI4. This is the first time that the interaction between these two proteins has been described and studied. Our findings could be of importance to understand the development of tumors, where PKP1 and PADI4 are involved. Moreover, our findings pave the way to describe the formation of neutrophil extracellular traps (NETs), whose construction is modulated by PADI4, and which mediate the proteolysis of cell-cell junctions where PKP1 intervenes.

Extracellular vesicles (EVs) are produced by almost all cell types in vivo or in vitro. Among them, exosomes are small nanovesicles with a lipid bilayer, proteins and RNAs actively involved in cellular communication, suggesting that they may be used both as biomarkers and for therapeutic purposes in diseases such as cancer. Moreover, the idea of using them as drug delivery vehicle arises as a promising field of study. Here, we reviewed recent findings showing the importance of EVs, with special focus in exosomes as biomarkers including the most relevant proteins found in different cancer types and it is discussed the FDA approved tests which use exosomes in clinical practice. Finally, we present an overview of the different chimeric EVs developed in the last few years, demonstrating that they can be conjugate to nanoparticles, biomolecules, cancer drugs, etc., and can be developed for a specific cancer treatment. Additionally, we summarized the clinical trials where EVs are used in the treatment of several cancer types aiming to improve the prognosis of these deadly diseases.